Note: Descriptions are shown in the official language in which they were submitted.
CA 02726300 2010-12-22
HT RECEPTOR MEDIATED NEUROGENESIS
RELATED APPLICATIONS
[00011 This application is a continuation-in-part application of U.S.
Application
11/746,008, filed May 8, 2007, now pending, which claims benefit of priority
under 35 USC
119(e) to U.S. Provisional Applications 60/746,878, filed May 9, 2006, now
abandoned,
60/805,436, filed June 21, 2006, now abandoned, and 60/882,429, filed December
28, 2006,
now abandoned, all of which are incorporated by reference as if fully set
forth.
FIELD OF THE DISCLOSURE
[00021 The instant disclosure relates to methods for treating diseases and
conditions of the
central and peripheral nervous system by stimulating or increasing
neurogenesis via use of a
5HT receptor modulator in combination with a neurogenic agent, neurogenic
sensitizing
agent or an anti-astrogenic agent, or another 5HT receptor modulator. The
disclosure
includes methods based on the application of a 5HT receptor modulator in
combination with
a neurogenic sensitizing agent or an anti-astrogenic agent to stimulate or
activate the
formation of new nerve cells.
BACKGROUND OF THE DISCLOSURE
[00031 Neurogenesis is a vital process in the brains of animals and humans,
whereby new
nerve cells are continuously generated throughout the life span of the
organism. The newly
born cells are able to differentiate into functional cells of the central
nervous system and
integrate into existing neural circuits in the brain. Neurogenesis is known to
persist
throughout adulthood in two regions of the mammalian brain: the subventricular
zone (SVZ)
of the lateral ventricles and the dentate gyrus of the hippocampus. In these
regions,
multipotent neural progenitor cells (NPCs) continue to divide and give rise to
new functional
neurons and glial cells (for review Jacobs Mol Psychiatry. 2000 May;5(3):262-
9). It has been
shown that a variety of factors can stimulate adult hippocampal neurogenesis,
e.g.,
adrenalectomy, voluntary exercise, enriched environment, hippocampus dependent
learning
and anti-depressants (Yehuda. J Neurochem. 1989 Jul;53(1):241-8, van Praag.
Proc Natl
Acad Sci U S A. 1999 Nov 9;96(23):13427-31, Brown. J Eur J Neurosci. 2003
May;17(10):2042-6, Gould. Science. 1999 Oct 15;286(5439):548-52, Malberg. J
Neurosci.
2000 Dec 15;20(24):9104-10, Santarelli. Science. 2003 Aug 8;301(5634):805-9).
Other
factors, such as adrenal hormones, stress, age and drugs of abuse negatively
influence
neurogenesis (Cameron. Neuroscience. 1994 Jul;61(2):203-9, Brown.
1
CA 02726300 2010-12-22
Neuropsychopharmacology. 1999 Oct;21(4):474-84, Kuhn. J Neurosci. 1996 Mar
15;16(6):2027-33, Eisch. Am J Psychiatry. 2004 Mar; 161(3):426).
[0004] Serotonin (5-hydroxytryptamine, 5-HT or 5HT) has been proposed to
assert its
effects through a number of membrane-bound receptors. The 5-HT or 5HT family
of
receptors includes 7 subfamilies with multiple subtypes within each family.
All members of
the 5HT family of receptors, with the exception of the 5HT3 receptor, belong
to the G
protein-coupled receptor (GPCR) superfamily. The 5HTla receptor subfamily with
the
5HT1 a (or serotonin) receptor subtype has been one of the most studied
receptors of the 5HT
family. According to some studies, 5HTla receptor agonists are thought to
inhibit activation
of adenylate cyclase in some cells, leading to decreases in cAMP. Another
study suggests
that the 5HTIa receptor is coupled to N- and L-type calcium channels in some
ganglion cells
(see Cardenas et al. J. Neurophysiol. 77(6):3284-96, 1997).
[0005] 5HTIa receptors are distributed in the CNS, and their activation has
been shown to
lead to neuronal hyperpolarization. The role of 5HT1a receptors has been
thought to relate to
modulation of anxiety, in part because knockout mice lacking 5HTIa receptors
display
increased anxiety. The animals also display reduced immobility in forced
swimming and tail
suspension tests. Agonists of 5HTIa, such as buspirone or gepirone, have been
used as
anxiolytics (see Tunnicliff Pharmacol. Toxicol. 69:149, 1991; and Den Boer et
al. Hum
Psychopharmacol. 15:315, 2000). Another 5HTIa agonist is 8-hydroxy-2-(di-n-
propylamino), where the R(+)-isomer is a full agonist and the S(-)-enantiomer
is a partial
agonist.
[0006] Antagonists of 5HT1 a may be used to accelerate the effects of
selective serotonin
reuptake inhibitors (SSRIs) and enhance their clinical efficacy (see
Arborelius et al. Naunyn-
Schmeiedebergs Arch Pharmacol 353:630-640, 1996). Examples of 5HTla
antagonists
include spiperone and pindolol.
[0007] The 5HT3 receptor is the only member of the 5HT family that is not a G
protein-
coupled receptor (GPCR). The 5HT3 receptor is a member of the superfamily of
ligand-gated
ion channels of which neuronal nicotinic acetylcholine receptors (nAChRs), and
the
inhibitory neurotransmitter receptors of GABA and glycine are also members.
The 5HT3
receptor consists of 5 subunits arranged around a central ion conducting pore
which is
permeable to sodium, potassium and calcium ions (Maricq et al, (1991) Science
254:432-7).
2
CA 02726300 2010-12-22
Binding of serotonin to the 5HT3 receptor opens the channel which in turn
leads to an
excitatory response in neurons. These excitatory effects are involved in
anxiety and emesis
(Thomson et al., (2007) Expert Opin Ther Targets 11:527-40).
[0008] The 5HT4 receptor is another 5HT subfamily, with multiple C-terminal
splice
variants having been described as 5HT4A through 5HT4H (see Blondel et al.
(1997) FEBS
Lett. 412:465; Blondel et al. (1998) J. Neurochem 70:2252; Claeysen et al.
(1997)
Neuroreport 8:3189; Claeysen et al. (1999) Mol. Pharmacol. 55:910; Van Den
Wyngaert et
al. (1997) J. Neurochem. 69:18 10; Mialet et al. (2000) Br. J. Pharmacol.
129:771; and Mialet
et al. (2000) Br. J. Pharmacol. 131:827. According to some studies, 5HT4
receptor agonists
have been observed as leading to increases in CAMP. The splice variants have
been reported
to couple positively to adenylyl cyclase and have been observed to have
similar
pharmacological properties.
[0009] 5HT4 receptors have been reported as displaying constitutive, agonist-
independent,
activity. The activity has been observed at relatively low receptor levels
which may explain
detected silent or inverse agonist activity by some putative antagonists.
[0010] Citation of the above documents is not intended as an admission that
any of the
foregoing is pertinent prior art. All statements as to the date or
representation as to the
contents of these documents is based on the information available to the
applicant and does
not constitute any admission as to the correctness of the dates or contents of
these documents.
BRIEF SUMMARY OF THE DISCLOSURE
[0011] Disclosed herein are compositions and methods for the prophylaxis and
treatment
of diseases, conditions and injuries of the central and peripheral nervous
systems by
stimulating or increasing neurogenesis. Aspects of the methods, and activities
of the
compositions, include increasing or potentiating neurogenesis in cases of a
disease, disorder,
or condition of the nervous system. Embodiments of the disclosure include
methods of
treating a neurodegenerative disorder, neurological trauma including brain or
central nervous
system trauma and/or recovery therefrom, affective disorder, psychosis,
learning and memory
disorders, and ischemia of the central and/or peripheral nervous systems. In
other
embodiments, the disclosed methods are used to improve cognitive outcomes and
mood
disorders.
3
CA 02726300 2010-12-22
[0012] In one aspect, methods of modulating, such as by stimulating or
increasing,
neurogenesis are disclosed. The neurogenesis may be at the level of a cell or
tissue. The cell
or tissue may be present in an animal subject or a human being, or
alternatively be in an in
vitro or ex vivo setting. In some embodiments, neurogenesis is stimulated or
increased in a
neural cell or tissue, such as that of the central or peripheral nervous
system of an animal or
human being. In cases of an animal or human, the methods may be practiced in
connection
with one or more disease, disorder, or condition of the nervous system as
present in the
animal or human subject. Thus, embodiments disclosed herein include methods of
treating a
disease, disorder, or condition by administering at least one neurogenesis
modulating agent
having activity against a 5HT receptor, hereinafter referred to as a "5HTR
agent." A 5HTR
agent may be formulated or used alone, in combination with another 5HTR agent,
or in
combination with one or more additional neurogenic agents.
[0013] While a 5HTR agent may be considered a "direct" agent in that it has
direct
activity against a 5HT receptor by interactions therewith, the disclosure
includes a 5HTR
agent that may be considered an "indirect" agent in that it does not directly
interact with a
5HT receptor. Thus, an indirect agent acts on a 5HT receptor indirectly, or
via production,
generation, stability, or retention of an intermediate agent which directly
interacts with a 5HT
receptor.
[0014] Embodiments of the disclosure include a combination of a 5HTR agent and
one or
more other neurogenic agents, or anti-astrogenic agents disclosed herein or
known to the
skilled person. An additional neurogenic agent as described herein may be a
direct 5HTR
agent, an indirect 5HTR agent, or a neurogenic agent that does not act,
directly or indirectly,
through a 5HT receptor. Thus in some embodiments, an additional neurogenic
agent is one
that acts, directly or indirectly, through a mechanism other than a 5HT
receptor. An
additional neurogenic agent as described herein may be one which acts through
a known
receptor or one which is known for the treatment of a disease or condition.
The disclosure
further includes a composition comprising a combination of a 5HTR agent with
one or more
other neurogenic agents, or anti-astrogenic agent. The anti-astrogenic agent
may be
neurogenic or may demonstrate little or no neurogenesis on its own but
inhibits the additional
astrogenesis associated with a compound such as that seen with many 5HTR
agents. When
the anti-astrogenic agent is used in combination with a compound (5HTR agent)
having
astrogenic properties, the neurogenesis associated with the combination may be
synergistic or
4
CA 02726300 2010-12-22
additive when compared to the neurogenesis observed for the respective
concentrations of the
combined agents alone or may remain unchanged from the respective
concentration of the
astrogenic agent alone but the astrogenesis will be decreased. The
neurogenesis and
astrogenesis observed with the combination will now be similar to that
observed for an
antidepressant such as an SSRI.
[0015] In a second aspect, there are provided methods of treating an affective
disorder in a
subject or patient by administering to the subject or patient first agent in
combination with a
second agent that reduces or suppresses proliferation or differentiation of
astrocytes caused
by the first agent, thereby treating the affective disorder. In some
embodiments, neurogenesis
is induced or increased by the administration of the first agent in
combination with the second
agent, as compared to the administration of the first agent alone. The first
agent may or may
not be neurogenic when administered alone. In some embodiments, the second
agent is not
neurogenic when administered alone. In particular embodiments, the first agent
is a 5HTR
agent. In certain embodiments, the second agent is selected from the group
consisting of a
modulator of a melatonin receptor, a GABA modulator, an al adrenergic receptor
modulator,
an opioid agent, a psycho stimulant, a norepinephrine and dopamine reuptake
inhibitor, folic
acid, and a folic acid derivative.
[0016] In a third aspect, there are provided methods of making efficacious or
improving
the efficacy of an astrogenic compound by reducing or suppressing
proliferation or
differentiation of astrocytes in treatment of a subject having an affective
disorder. Such
methods include administering to the subject the astrogenic compound with a
second agent
that reduces or suppresses proliferation or differentiation of astrocytes in
the subject, wherein
the compound in combination with the second agent has efficacy or improved
efficacy in
treating an affective disorder as compared to treatment with the compound
alone. Additional
embodiments include methods wherein the astrogenic compound may be the source
of the
increased astrocytes and the second agent is provided to reduce or suppress
the proliferation
or differentiation of astrocytes in the subject to be treated. In some
embodiments, the
compound has no efficacy in treating an affective disorder. In particular
embodiments, the
astrogenic compound is a 5HTR agent. In certain embodiments, the second agent
is selected
from the group consisting of a modulator of a melatonin receptor, a GABA
modulator, an al
adrenergic receptor modulator, an opioid agent, a psychostimulant, a
norepinephrine and
dopamine reuptake inhibitor, folic acid, and a folic acid derivative.
CA 02726300 2010-12-22
[0017] In still another aspect, there are provided methods of improving the
efficacy of an
astrogenic compound in treatment of a subject with a psychiatric condition.
Such methods
include administering the compound and administering an agent that reduces the
number of
astrocytes, to the subject, wherein the administration of the agent improves
the efficacy of the
compound when compared to the efficacy of the compound alone. In particular
embodiments, the astrogenic compound is a 5HTR agent. In certain embodiments,
the agent
which reduces the number of astrocytes is selected from the group consisting
of a modulator
of a melatonin receptor, a GABA modulator, an al adrenergic receptor
modulator, an opioid
agent, a psychostimulant, a norepinephrine and dopamine reuptake inhibitor,
folic acid, and a
folic acid derivative.
[0018] In another aspect, there are provided methods of improving the efficacy
of a 5HTR
agent in treating a subject or patient with a psychiatric condition by
administering the 5HTR
agent with a second agent to the subject or patient, wherein the efficacy of
the 5HTR agent in
combination is improved relative to the efficacy of the 5HTR agent used
individually. In
some embodiments, the combination is administered at a dosage that would be
sub-
therapeutic for either agent individually. In other embodiments, the
combination is
administered less frequently relative to the use of either agent individually.
In certain
embodiments, the 5HTR agent is selected from the group consisting of a 5HTIa
agonist, a
5HT3 antagonist, and a 5HT4 agonist. In particular embodiments, the second
agent is
selected from the group consisting of a modulator of a melatonin receptor, a
GABA
modulator, an al adrenergic receptor modulator, an opioid agent, a
psychostimulant, a
norepinephrine and dopamine reuptake inhibitor, and folic acid or a derivative
thereof.
[0019] In still another aspect, there are provided methods of improving
efficacy of a
5HTR agent in treating a psychiatric condition in a subject by administering
to the subject the
5HTR agent in combination with an agent that inhibits, reduces, or prevents
astrogenesis,
thereby improving the efficacy of the 5HTR agent. In certain embodiments, the
5HTR agent
is selected from the group consisting of a 5HT1 a agonist, a 5HT3 antagonist,
and a 5HT4
agonist. In particular embodiments, the agent that inhibits, reduces, or
prevents astrogenesis
is selected from the group consisting of a modulator of a melatonin receptor,
a GABA
modulator, an al adrenergic receptor modulator, an opioid agent, a psycho
stimulant, a
norepinephrine and dopamine reuptake inhibitor, and folic acid or a derivative
thereof.
6
CA 02726300 2010-12-22
[0020] In a further aspect, there are provided methods of converting an
astrogenic 5HTR
compound from a non-antidepressant agent to an antidepressant agent by adding
an agent
which reduces the astrogenesis of the 5HTR compound. In particular
embodiments, the
astrogenic 5HTR compound is selected from the group consisting of a 5HT1a
agonist, a
5HT3 antagonist, and a 5HT4 agonist. In certain embodiments, the agent which
reduces the
astrogenesis of the 5HTR compound is selected from the group consisting of a
modulator of a
melatonin receptor, a GABA modulator, an al adrenergic receptor modulator, an
opioid
agent, a psychostimulant, a norepinephrine and dopamine reuptake inhibitor,
folic acid, and a
folic acid derivative.
[0021] In still another aspect, there are provided methods of modifying
neurogenic
activity of a 5HTR agent by combining the 5HTR agent with an anti-astrogenic
agent,
wherein the 5HTR agent in combination has enhanced neurogenic activity as
compared to the
neurogenic activity of the 5HTR agent alone. In particular embodiments, the
5HTR agent is
selected from the group consisting of a 5HTla agonist, a 5HT3 antagonist, and
a 5HT4
agonist. In certain embodiments, the anti-astrogenic agent is selected from
the group
consisting of a modulator of a melatonin receptor, a GABA modulator, an a I
adrenergic
receptor modulator, an opioid agent, a psychostimulant, a norepinephrine and
dopamine
reuptake inhibitor, folic acid, and a folic acid derivative.
[0022] In yet another aspect, there are provided methods of increasing the
number of
neurons in a cell population or tissue, wherein the method includes contacting
the cell
population or tissue with a 5HTR agent and a second agent that reduces or
suppresses the
amount or level of astrogenesis, thereby increasing number of neurons in the
cell population
or tissue. In some embodiments, expression of TUJ-1 is increased in the cell
population or
tissue. In particular embodiments, expression of GFAP is decreased in the cell
population or
tissue. In certain embodiments, the first agent is a 5HTR agent. In some
embodiments, the
second agent is selected from the group consisting of a modulator of a
melatonin receptor, a
GABA modulator, an al adrenergic receptor modulator, an opioid agent, a
psychostimulant,
a norepinephrine and dopamine reuptake inhibitor, folic acid, and a folic acid
derivative.
[0023] In another aspect, there are provided methods of decreasing the level
of
astrogenesis in a cell or cell population, the method comprising contacting
the cell or cell
population with an astrogenic 5HTR agent and a second agent that reduces or
suppresses the
amount or level of astrogenesis caused by the 5HTR agent, thereby decreasing
the level of
7
CA 02726300 2010-12-22
astrogenesis in the cell or cell population. In some embodiments, the 5HTR
agent is selected
from the group consisting of a 5HT1a agonist, a 5HT3 antagonist, and a 5HT4
agonist. In
certain embodiments, the second agent is selected from the group consisting of
a modulator
of a melatonin receptor, a GABA modulator, an a1 adrenergic receptor
modulator, an opioid
agent, a psychostimulant, a norepinephrine and dopamine reuptake inhibitor,
and folic acid or
a derivative thereof.
[0024] In a further aspect, the disclosure includes a method of lessening
and/or reducing a
decline or decrease of cognitive function in a subject or patient. In some
cases, the method
may be applied to maintain and/or stabilize cognitive function in the subject
or patient. The
method may comprise administering a 5HTR agent, in combination with one or
more other
neurogenic agents, or anti-astrogenic agent, to a subject or patient in an
amount effective to
lessen or reduce a decline or decrease of cognitive function.
[0025] In an additional aspect, the disclosure includes a method of treating
mood disorders
with use of a 5HTR agent, in combination with one or more other neurogenic
agents, or anti-
astrogenic agent. In some embodiments, the method may be used to moderate or
alleviate a
mood disorder in a subject or patient. Non-limiting examples include a subject
or patient
having, or diagnosed with, a disease or condition as described herein. In
other embodiments,
the method may be used to improve, maintain, or stabilize mood in a subject or
patient. Of
course the method may be optionally combined with any other therapy or
condition used in
the treatment of a mood disorder.
[0026] In another aspect, the disclosed methods include identifying a patient
suffering
from one or more diseases, disorders, or conditions, or a symptom thereof, and
administering
to the patient a 5HTR agent, in combination with one or more other neurogenic
agents, or
anti-astrogenic agent, as described herein. In some embodiments, a method
including
identification of a subject as in need of an increase in neurogenesis, and
administering to the
subject a 5HTR agent, in combination with one or more other neurogenic agents,
or anti-
astrogenic agent is disclosed herein. In other embodiments, the subject is a
patient, such as a
human patient.
[0027] Another aspect of the disclosure describes a method including
administering a
5HTR agent, in combination with one or more other neurogenic agents, or anti-
astrogenic
agent, to a subject exhibiting the effects of insufficient amounts of, or
inadequate levels of,
8
CA 02726300 2010-12-22
neurogenesis. In some embodiments, the subject may be one that has been
treated with an
agent that decreases or inhibits neurogenesis. Non-limiting examples of an
inhibitor of
neurogenesis include opioid receptor agonists, such as a mu receptor subtype
agonist like
morphine. In other cases, the need for additional neurogenesis is that
detectable as a
reduction in cognitive function, such as that due to age-related cognitive
decline, Alzheimer's
Disease, epilepsy, or a condition associated with epilepsy as non-limiting
examples.
[0028] In a related manner, a method may include administering a 5HTR agent,
in
combination with one or more other neurogenic agents, or anti-astrogenic
agent, to a subject
or person that will be subjected to an agent that decreases or inhibits
neurogenesis. Non-
limiting embodiments include those where the subject or person is about to be
administered
morphine or another opioid receptor agonist, like another opiate, and so about
to be subject to
a decrease or inhibition of neurogenesis. Non-limiting examples include
administering a
5HTR agent, in combination with one or more other neurogenic agents, or anti-
astrogenic
agent, to a subject before, simultaneously with, or after the subject is
administered morphine
or other opiate in connection with a surgical procedure.
[0029] In another aspect, the disclosure includes methods for preparing a
population of
neural stem cells suitable for transplantation, comprising culturing a
population of neural
stem cells (NSCs) in vitro, and contacting the cultured neural stem cells with
a 5HTR agent,
in combination with one or more other neurogenic agents, or anti-astrogenic
agent. In some
embodiments, the stem cells are prepared and then transferred to a recipient
host animal or
human. Non-limiting examples of preparation include 1) contact with a 5HTR
agent, in
combination with one or more other neurogenic agents, or anti-astrogenic
agent, until the
cells have undergone neurogenesis, such as that which is detectable by visual
inspection,
marking, or cell counting, or 2) contact with a 5HTR agent, in combination
with one or more
other neurogenic agents, or anti-astrogenic agent, until the cells have been
sufficiently
stimulated or induced toward or into neurogenesis. The cells prepared in such
a non-limiting
manner may be transplanted to a subject, optionally with simultaneous, nearly
simultaneous,
or subsequent administration of another neurogenic agent to the subject. While
the neural
stem cells may be in the form of an in vitro culture or cell line, in other
embodiments, the
cells may be part of a tissue which is subsequently transplanted into a
subject.
[0030] In yet another aspect, the disclosure includes methods of modulating,
such as by
stimulating or increasing, neurogenesis in a subject by administering a 5HTR
agent, in
9
CA 02726300 2010-12-22
combination with one or more other neurogenic agents, or anti-astrogenic
agent. In some
embodiments, the neurogenesis occurs in combination with the stimulation of
angiogenesis
which provides new cells with access to the circulatory system.
[0031] Another aspect of the disclosure include methods and compositions
wherein two or
more 5HTR agents are utilized, such as combinations of buspirone, azasetron,
clozapine,
cisapride, ondansetron, tandospirone, granisetron, ondansetron, mosapride,
sumatriptan,
agomelatine and the like. Also disclosed are 5HTR agents in combination with a
melatonin
receptor modulator such as melatonin or ramelteon; an opioid agent, such as
naltrexone or
naloxone; a GABA agent, such as baclofen or gabapentin; an al adrenergic
receptor
modulator such as modafinil or armodafinil; a norepinephrin/dopamine inhibitor
such as
buproprion; a natural product or derivative such as folic acid or
methylfolate; and/or a
psychostimulant such as methylphenidate. The anti-astrogenic agents to be used
in
combination with the 5HTR agents may be a melatonin receptor modulator, such
as
melatonin or ramelteon; an opiod agent such as naltrexone or naloxone; a GABA
agent, such
as baclofen or gabapentin; an a 1 adrenergic receptor modulator such as
modafinil or
armodafinil; a natural product or derivative such as folic acid or
methylfolate; and/or a
psychostimulant such as methylphenidate.
[0032] Prefered combinations include buspirone, azasetron, ondansetron or
granisetron
with baclofen, naltrexone, folic acid, methyl folate, gabapentin,
methylphenidate, or
buproprion. In addition, the combination of agents can be administered in one
formulation,
or concurrently or sequentially in more than one formulation. A preferred
nervous system
disorder is an affective disorder.
[0033] The details of additional embodiments are set forth in the accompanying
drawings
and the description below. Other features, objects, and advantages of the
embodiments will
be apparent from the drawings and detailed description, and from the claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0034] FIG. 1 is a dose-response curve showing effect of the neurogenic agent
5-HTP (5-
hydroxytryptophan, a serotonin precursor) on neuronal differentiation of human
neural stem
cells. Data is presented as the percentage of the neuronal positive control,
with basal media
values subtracted. EC50 was observed at a 5-HTP concentration of 12.0 M in
test cells,
compared to 4.7 M for the positive control compound.
CA 02726300 2010-12-22
100351 FIG. 2 is a dose-response curve showing the astrogenic effect of the
neurogenic
agent 5-HTP on human neural stem cells. Astrocyte differentiation data is
presented as the
percentage of the astrocyte positive control, with basal media values
subtracted. EC50 was
undeterminable for 5-HTP (greater than concentrations tested), compared to
19.9 M for the
positive control compound.
[00361 FIG. 3 is a series of immunofluorescent microscopic images of
monolayers of
human neural stem cells (hNSC) after immunohistochemistry staining with the
neuronal
marker TUJ-1 (green), the astrocyte marker GFAP (red), and a nuclear cell
marker (Hoechst
33342 in blue). The upper left image is a negative control (basal media), the
upper middle
image is a neuronal positive control (basal media plus a known promoter of
neuronal
differentiation), and the upper right image is an astrocyte positive control
(basal media plus a
known inducer of astrocyte differentiation). The lower image shows the effect
of 10.0 M 5-
HTP on hNSC differentiation.
[00371 FIG. 4 is a dose-response curve showing effect of the agent buspirone,
a 5-HTIA
agonist, on neuronal differentiation of human neural stem cells. Data is
presented as the
percentage of the neuronal positive control, with basal media values
subtracted. EC50 was
observed at a buspirone concentration of 22.8 M in test cells, compared to
4.7 M for the
positive control compound.
100381 FIG. 5 is a dose-response curve showing the astrogenic effect of the
agent
buspirone, a 5-HT1A agonist, on human neural stem cells. Astrocyte
differentiation data is
presented as the percentage of the astrocyte positive control, with basal
media values
subtracted. EC50 was observed at a buspirone concentration of 13.24 M in test
cells,
compared to 19.9 M for the positive control compound.
[00391 FIG. 6 is a series of immunofluorescent microscopic images of
monolayers of
human neural stem cells (hNSC) after immunohistochemistry staining with the
neuronal
marker TUJ-1 (green), the astrocyte marker GFAP (red), and a nuclear cell
marker (Hoechst
33342 in blue). The upper left image is a negative control (basal media), the
upper middle
image is a neuronal positive control (basal media plus a known promoter of
neuronal
differentiation), and the upper right image is an astrocyte positive control
(basal media plus a
known inducer of astrocyte differentiation). The lower image shows the effect
of 31.6 M
buspirone on hNSC differentiation.
11
CA 02726300 2010-12-22
[00401 FIG. 7 is a dose-response curve showing effect of the agent
tandospirone, a 5-
HT1A agonist, on neuronal differentiation of human neural stem cells. Data is
presented as
the percentage of the neuronal positive control, with basal media values
subtracted. EC50 was
observed at a tandospirone concentration of 12.05 M in test cells, compared
to 4.7 gM for
the positive control compound.
[00411 FIG. 8 is a dose-response curve showing the astrogenic effect of the
agent
tandospirone, a 5-HT1A agonist. Astrocyte differentiation data is presented as
the percentage
of the astrocyte positive control, with basal media values subtracted. EC50
was observed at a
tandospirone concentration of 8.69 M in test cells, compared to 19.9 M for
the positive
control compound.
[00421 FIG. 9 is a series of immunofluorescent microscopic images of
monolayers of
human neural stem cells (hNSC) after immunohistochemistry staining with the
neuronal
marker TUJ- I (green), the astrocyte marker GFAP (red), and a nuclear cell
marker (Hoechst
33342 in blue). The upper left image is a negative control (basal media), the
upper middle
image is a neuronal positive control (basal media plus a known promoter of
neuronal
differentiation), and the upper right image is an astrocyte positive control
(basal media plus a
known inducer of astrocyte differentiation). The lower image shows the effect
of 31.6 M
tandospirone on hNSC differentiation.
[00431 FIG. 10 shows the effects of fluoxetine, a selective serotonin reuptake
inhibitor, or
SSRI, on behavior in the Novel Object Recognition (NOR) cognition assay. Data
is
presented as the mean percentage of the visits to the novel object in FIG. I0A
and mean
percentage of the number of time spent (same scale) with the novel object in
FIG. IOB. The
treatment populations were administered vehicle or fluoxetine at 5 and 10
mg/kg. The 10
mg/kg data in each panel are at p < 0.05. Fluoxetine increased both the number
of visits to,
and the amount of time spent with, the novel object, demonstrating a dose-
dependent increase
in cognition.
[00441 FIG. 11 shows the effects of fluoxetine, a selective serotonin reuptake
inhibitors, or
SSRI, on behavior in the novelty suppressed feeding (NSF) chronic depression
assay. Data is
presented as the latency to eat (or feed), on a scale from 0 to 300 seconds,
at intervals of 50
seconds, after treatment with vehicle or 10 mg/kg fluoxetine, with the latter
at p < 0. 05, upon
a novel food.
12
CA 02726300 2010-12-22
[0045] FIG. 12 shows the effects of buspirone, a 5-HT1A agonist, on behavior
in the
Novel Object Recognition (NOR) cognition assay. Data is presented as the mean
percentage
of the visits to the novel object in FIG. 12A and mean percentage of the
number of time spent
(same scale) with the novel object in FIG. 12B. The treatment populations were
administered
vehicle or buspirone at 0.5 and 5.0 mg/kg. Buspirone did not demonstrate a
significant effect
on cognition.
[0046] FIG. 13 shows the effects of buspirone, a 5-HT1A agonist, on behavior
in the
novelty suppressed feeding (NSF) chronic depression assay. Data is presented
as the latency
to eat (feed), in seconds, upon a novel food. The treatment populations were
administered
vehicle or buspirone at 0.5 and 5.0 mg/kg. The 0.5 mg/kg data are at p = 0.08.
Buspirone did
not demonstrate a significant effect on novelty suppressed feeding.
[0047] FIG. 14 shows the effects of buspirone, a 5-HT1A agonist, on rat body
weight
during chronic dosing. Data is presented as the mean body weight in grams per
day (vertical
axis) starting with on the first day of dosing. Animals treated with buspirone
showed a dose-
dependent decrease in mean body weight.
[0048] FIG. 15 is a dose-response curve showing enhancement of the effects of
the agent
dopamine on neuronal differentiation of human neural stem cells by combination
with a 5-
HT1A agonist (5-HTP). Data is presented as the percentage of the neuronal
positive control,
with basal media values subtracted. Increased efficacy was observed with a
combination of
dopamine and 10 M 5-HTP or 30 M 5-HTP than with dopamine alone.
[0049] FIG. 16 contains representations of the structures of some non-limiting
neurogenic
sensitizing agents of the invention.
100501 FIG. 17 is a dose-response curve showing effect of the neurogenic
agents
buspirone (5HTI a receptor agonist) and melatonin (melatonin receptor agonist)
in
combination on neuronal differentiation of human neural stem cells compared to
the effect of
either agent alone. When run independently, each compound was tested in a
concentration
response curve ranging from 0.01 gM to 31.6 M. In combination, the compounds
were
combined at equal concentrations at each point (for example, the first point
in the combined
curve consisted of a test of 0.01 M buspirone and 0.01 M melatonin). Data is
presented as
the percentage of the neuronal positive control, with basal media values
subtracted. When
used alone, EC50 was observed at a buspirone concentration of 9.4 M or a
melatonin
13
CA 02726300 2010-12-22
concentration of >31.6 M (estimated based on extrapolation to be
approximately at 49.7
M) in test cells. When used in combination, neurogenesis is greatly enhanced:
EC50 was
observed at a combination of buspirone and melatonin at concentrations of 2.2
M each.
[00511 FIG. 18 is a dose-response curve showing effect of the agents buspirone
(5HTIa
receptor agonist) and melatonin (melatonin receptor agonist) in combination on
astrocyte
differentiation of human neural stem cells compared to the effect of either
agent alone. When
run independently, each compound was tested in a concentration response curve
ranging from
0.01 M to 31.6 M. In combination, the compounds were combined at equal
concentrations
at each point (for example, the first point in the combined curve consisted of
a test of 0.01
M buspirone and 0.01 M melatonin). Data is presented as the percentage of the
astrocyte
positive control, with basal media values subtracted. When used alone, EC50
was observed at
a buspirone concentration of 5.7 M or a melatonin concentration of >31.6 M
(no
estimation possible to lack of observed effect) in test cells. When used in
combination, EC50
was greater than all tested concentrations (>31.2 M) and astrocyte
differentiation was
reduced from a maximum of 60% with buspirone alone to a maximum of 12% with
the
combination of buspirone and melatonin.
100521 FIG. 19 shows the effects of buspirone alone, melatonin alone, and the
combination of the two drugs on antidepressant activity in the novelty
suppressed feeding
assay. Male F344 rats were dosed lx per day for 21-days with 0 (vehicle only),
0.5 mg/kg
buspirone (n = 12 per dose group, i.p.), 3.0 mg/kg melatonin (n = 12 per dose
group, i.p.) or
the combination of the two drugs at the same doses. Behavioral testing was
carried out as
described in Example 14. Results shown in this figure indicate the mean
latency to approach
and eat a food pellet within the novel environment. Data are presented as
latency to eat
expressed as percent baseline. Melatonin or buspirone alone did not
significantly reduce the
latency to eat the food pellet. The combination of melatonin and buspirone
resulted in a
significant decrease in latency to eat the food pellet. The data indicate that
the combination
of buspirone and melatonin at doses that do not produce antidepressant
activity when dosed
alone, result in significant antidepressant activity when administered in
combination.
100531 FIG. 20 shows the effects of buspirone alone, melatonin alone, and the
combination of the two drugs on in vivo neurogenesis. Male F344 rats were
dosed lx per day
for 28-days with 0 (vehicle only), 0.5 mg/kg buspirone (n = 12 per dose group,
i.p.), 3.0
mg/kg melatonin (n = 12 per dose group, ip) or the combination of the two
drugs at the same
14
CA 02726300 2010-12-22
doses. BrdU was administered once daily between days 9 and 14 (100mg/kg/day,
i.p., n=12
per dose group). The results show BrdU positive cell counts within the granule
cell layer of
the dentate gyrus. Data are presented as percent change in BrdU positive cells
per cubic mm
dentate gyrus. Melatonin or buspirone alone did not significantly change the
number of
BrdU positive cells. The combination of melatonin and buspirone resulted in a
significant
increase in BrdU positive cells compared to vehicle.
[0054] FIG. 21 shows the effect of chronic dosing of rats with melatonin,
buspirone, or a
combination of both agents on body weight (circle: vehicle; triangle: 3.0
mg/kg melatonin;
diamond: 10.0 mg/kg melatonin; square: 3.0 mg/kg melatonin + 0.5 mg/kg
buspirone). The
combination of melatonin and buspirone resulted in decreased body weight
compared to
vehicle treated animals. Results are presented as the mean body weight over
days.
[0055] FIG. 22 is a dose-response curve showing effect of the neurogenic
agents
buspirone (5HT1a receptor agonist) and baclofen (GABA receptor agonist) in
combination
on neuronal differentiation of human neural stem cells compared to the effect
of either agent
alone. When run independently, each compound was tested in a concentration
response
curve ranging from 0.01 gM to 31.6 M. In combination, the compounds were
combined at
equal concentrations at each point (for example, the first point in the
combined curve
consisted of a test of 0.01 M buspirone and 0.01 gM baclofen). Data is
presented as the
percentage of the neuronal positive control, with basal media values
subtracted. When used
alone, maximal neuronal differentiation was 62% for buspirone and 74% for
baclofen. When
combined, the maximal neuronal differentiation was 103%.
[0056] FIG. 23 is a dose-response curve showing effect of the agents buspirone
(5HTIa
receptor agonist) and baclofen (GABA receptor agonist) in combination on
astrocyte
differentiation of human neural stem cells compared to the effect of either
agent alone. When
run independently, each compound was tested in a concentration response curve
ranging from
0.01 M to 31.6 M. In combination, the compounds were combined at equal
concentrations
at each point (for example, the first point in the combined curve consisted of
a test of 0.01
pM buspirone and 0.01 pM baclofen). Data is presented as the percentage of the
neuronal
positive control, with basal media values subtracted. When used alone, EC50
was observed at
a buspirone concentration of 5.7 M or a baclofen concentration of >31.6 pM
(no estimation
possible to lack of observed effect) in test cells. When used in combination,
EC50 was greater
than all tested concentrations (>31.2 M) and astrocyte differentiation was
reduced from a
CA 02726300 2010-12-22
maximum of 60% with buspirone alone to a maximum of 14% with the combination
of
buspirone and baclofen.
[0057] FIG. 24 is a dose-response curve showing the effect of azasetron (5HT3
receptor
antagonist) (squares) on the differentiation of cultured human neural stem
cells (hNSCs)
along a neuronal lineage. Background media values are subtracted and data is
normalized
with respect to a neuronal positive control (circles). Azasetron significantly
promoted
neuronal differentiation, with an EC50 value of approximately 17.8 gM compared
to an EC50
for the positive neuronal control of approximately 6.3 M.
[0058] FIG. 25 is a dose-response curve showing the effect of azasetron
(squares) on the
differentiation of cultured human neural stem cells (hNSCs) along an astrocyte
lineage.
Background media values are subtracted and data is normalized with respect to
an astrocyte
positive control. Azasetron did not show a significant effect on astrocyte
differentiation
within the range of concentrations tested (EC50 value greater than highest
concentration tested
(31.6 M)). In light of the results shown in Fig. 24, azasetron preferentially
promotes
differentiation of hNSCs along a neuronal lineage.
[0059] FIG. 26 is dose-response curve showing the effect of azasetron
(squares) on the
cell count of cultured human neural stem cells (hNSCs). Data is shown as a
percent of the
basal media cell count. Toxic doses typically cause a reduction of the basal
cell count below
80%. Azasetron had no detectable toxicity at concentrations up to 31.6 M.
[0060] FIG. 27 is an immunofluorescent microscopic image of a monolayer of
human
neural stem cells (hNSC) incubated with 30 M azasetron and stained with the
neuronal
marker TUJ-1, the astrocyte marker GFAP, and a nuclear cell marker (Hoechst
33342). The
hNSC comprising the monolayer are primarily of a neuronal lineage.
[0061] FIG. 28 is a full eight (8) point concentration-response curve showing
effects of
the 5-HT3 receptor antagonist, azasetron, on neuronal differentiation of human
neural stem
cells. Azasetron was tested in a concentration response curves ranging from
0.01 pM to 31.6
M. Data is presented as the percentage of the neuronal positive control, with
basal media
values subtracted. Azasetron induced neuronal differentiation in a
concentration dependent
manner with a maximum neuronal differentiation percent of positive control 57%
with an
EC50 of 4.4 M.
16
CA 02726300 2010-12-22
[0062] FIG. 29 is a dose-response curve showing effect of the 5-HT3 receptor
antagonist,
granisetron, on neuronal differentiation of human neural stem cells.
Granisetron was tested
in a concentration response curves ranging from 0.01 [tM to 31.6 M. Data is
presented as
the percentage of the neuronal positive control, with basal media values
subtracted.
Granisetron induced neuronal differentiation in a concentration dependent
manner with a
maximum neuronal differentiation 73% of positive control with an EC50 of 1.2
M.
[0063] FIG. 30 is a dose-response curve showing effect of the 5-HT3 receptor
antagonist,
ondansetron, on neuronal differentiation of human neural stem cells.
Ondansetron was tested
in a concentration response curves ranging from 0.01 M to 31.6 M. Data is
presented as
the percentage of the neuronal positive control, with basal media values
subtracted.
Ondansetron induced neuronal differentiation in a concentration dependent
manner with a
maximum neuronal differentiation 60% of positive control with an EC50 of 23.9
M.
[0064] FIG. 31 is a dose-response curve showing the effect of mosapride
citrate (5-HT4
receptor agonist) (squares) on the differentiation of cultured human neural
stem cells
(hNSCs) along a neuronal lineage. Background media values are subtracted and
data is
normalized with respect to a neuronal positive control (circles). Mosapride
citrate
significantly promoted neuronal differentiation, with an EC50 value of
approximately 15.8
M, compared to an EC50 for the positive neuronal control of approximately 6.3
M.
[0065] FIG. 32 is a dose-response curve showing the effect of mosapride
citrate (squares)
on the differentiation of cultured human neural stem cells (hNSCs) along an
astrocyte
lineage. Background media values are subtracted and data is normalized with
respect to an
astrocyte positive control. Mosapride citrate did not show a significant
effect on astrocyte
differentiation within the range of concentrations tested (EC50 value greater
than highest
concentration tested (31.6 M)). In light of the results shown in Fig. 31,
mosapride citrate
preferentially promotes differentiation of hNSCs along a neuronal lineage.
[0066] FIG. 33 is dose-response curve showing the effect of mosapride citrate
(squares)
on the cell count of cultured human neural stem cells (hNSCs). Data is shown
as a percent of
the basal media cell count. Toxic doses typically cause a reduction of the
basal cell count
below 80%. Mosapride citrate had no detectable toxicity at concentrations up
to 31.6 M.
[0067] FIG. 34 is an immunofluorescent microscopic image of a monolayer of
human
neural stem cells (hNSC) incubated with 30 M mosapride citrate and stained
with the
17
CA 02726300 2010-12-22
neuronal marker TUJ-l, the astrocyte marker GFAP, and a nuclear cell marker
(Hoechst
33342). The hNSC comprising the monolayer are primarily of a neuronal lineage.
[0068] FIG. 35 is a full eight (8) point concentration-response curve showing
effects of
the 5-HT4 receptor agonist, mosapride citrate, on neuronal differentiation of
human neural
stem cells. Mosapride was tested in a concentration response curves ranging
from 0.01 M to
31.6 M. Data is presented as the percentage of the neuronal positive control,
with basal
media values subtracted. Mosapride induced neuronal differentiation in a
concentration
dependent manner with a maximum neuronal differentiation 92% of positive
control with an
EC50 of 10.4 M.
[0069] FIG. 36 is a dose-response curve showing effect of the 5-HT4 receptor
agonist,
cisapride, on neuronal differentiation of human neural stem cells. Cisapride
was tested in a
concentration response curves ranging from 0.01 gM to 31.6 M. Data is
presented as the
percentage of the neuronal positive control, with basal media values
subtracted. Cisapride
induced neuronal differentiation in a concentration dependent manner with a
maximum
neuronal differentiation 56% of positive control with an EC50 of 7.9 M.
[0070] FIG. 37 is a dose-response curve showing effect of the 5-HT1B/1D
receptor
agonist, sumatriptan, on neuronal differentiation of human neural stem cells.
Sumatriptan
was tested in a concentration response curves ranging from 0.01 M to 31.6 M.
Data is
presented as the percentage of the neuronal positive control, with basal media
values
subtracted. Sumatriptan induced neuronal differentiation in a concentration
dependent
manner with a maximum neuronal differentiation 76% of positive control with an
EC50 of
14.9 M.
[0071] FIG. 38 is a dose-response curve showing effect of the neurogenic
agent,
agomelatine (reported melatonin agonist and 5-HT2B/2C antagonist), on neuronal
differentiation. Agomelatine was tested in a concentration response curves
ranging from 0.01
M to 31.6 M. Data is presented as the percentage of the neuronal positive
control, with
basal media values subtracted. Agomelatine showed a maximum neuronal
differentiation
42% of positive control with an EC50 of 8.7 M.
[0072] FIG. 39 is a dose-response curve showing effect of the neurogenic
agents
buspirone (5HT1a receptor agonist) and modafinil in combination on neuronal
differentiation
of human neural stem cells compared to the effect of either agent alone. When
run
18
CA 02726300 2010-12-22
independently, each compound was tested in a concentration response curve
ranging from
0.01 uM to 31.6 uM. In combination, the compounds were combined at equal
concentrations
at each point (for example, the first point in the combined curve consisted of
a test of 0.01
uM buspirone and 0.01 uM modafinil). Data is presented as the percentage of
the neuronal
positive control, with basal media values subtracted. When used alone, EC50
was observed at
a buspirone concentration of 9.4 uM or a modafinil concentration of 12.5 uM in
test cells.
When used in combination, neurogenesis is maintained with EC50 observed at a
combination
of buspirone and modafinil at concentrations of 4.5 uM each.
100731 FIG. 40 is a dose-response curve showing effect of the agents buspirone
(5HT1 a
receptor agonist) and modafinil in combination on astrocyte differentiation of
human neural
stem cells compared to the effect of either agent alone. When run
independently, each
compound was tested in a concentration response curve ranging from 0.01 uM to
31.6 uM.
In combination, the compounds were combined at equal concentrations at each
point (for
example, the first point in the combined curve consisted of a test of 0.01 uM
buspirone and
0.01 uM modafinil). Data is presented as the percentage of the neuronal
positive control,
with basal media values subtracted. When used alone, EC50 was observed at a
buspirone
concentration of 5.7 uM or a modafinil concentration of >31.6 uM in test
cells. When used
in combination, EC50 was greater than all tested concentrations (>31.2 uM) and
astrocyte
differentiation was reduced from a maximum of 60% with buspirone alone to a
maximum of
28% with the combination of buspirone and modafinil.
100741 FIG. 41 is a dose-response curve showing effect of the neurogenic
agents azasetron
(5HT3 receptor antagonist) and buspirone (5HT1 a receptor agonist) in
combination on
neuronal differentiation of human neural stem cells compared to the effect of
either agent
alone. When run independently, each compound was tested in a concentration
response
curve ranging from 0.01 uM to 31.6 uM. In combination, the compounds were
combined at
equal concentrations at each point (for example, the first point in the
combined curve
consisted of a test of 0.01 uM azasetron and 0.01 uM buspirone). Data is
presented as the
percentage of the neuronal positive control, with basal media values
subtracted. When used
alone, EC50 was observed at an azasetron concentration of 5.8 uM or a
buspirone
concentration of 9.4 uM in test cells. When used in combination, neurogenesis
is greatly
enhanced. EC50 was observed at a combination of azasetron and buspirone at
concentrations
of 0.6 uM each, resulting a synergistic combination index of 0.18.
19
CA 02726300 2010-12-22
[0075] FIG. 42 is a dose-response curve showing effect of the neurogenic
agents azasetron
(5HT3 receptor antagonist) and baclofen (GABA receptor agonist) in combination
on
neuronal differentiation of human neural stem cells compared to the effect of
either agent
alone. When run independently, each compound was tested in a concentration
response
curve ranging from 0.01 uM to 31.6 uM. In combination, the compounds were
combined at
equal concentrations at each point (for example, the first point in the
combined curve
consisted of a test of 0.01 uM azasetron and 0.01 uM baclofen). Data is
presented as the
percentage of the neuronal positive control, with basal media values
subtracted. When used
alone, EC50 was observed at an azasetron concentration of 5.8 uM or a baclofen
concentration
of 3.9 uM in test cells. When used in combination, neurogenesis is greatly
enhanced. EC50
was observed at a combination of azasetron and baclofen at concentrations of
0.19 uM each,
resulting a synergistic combination index of 0.08.
[0076] FIG. 43 is a dose-response curve showing effect of the neurogenic
agents azasetron
(5HT3 receptor antagonist) and captopril (ACE inhibitor) in combination on
neuronal
differentiation of human neural stem cells compared to the effect of either
agent alone. When
run independently, each compound was tested in a concentration response curve
ranging from
0.01 uM to 31.6 uM. In combination, the compounds were combined at equal
concentrations
at each point (for example, the first point in the combined curve consisted of
a test of 0.01
uM azasetron and 0.01 uM captopril). Data is presented as the percentage of
the neuronal
positive control, with basal media values subtracted. When used alone, EC50
was observed at
an azasetron concentration of 5.8 uM or a captopril concentration of 5.4 uM in
test cells.
When used in combination, neurogenesis is greatly enhanced. EC50 was observed
at a
combination of azasetron and captopril at concentrations of 1.2 uM each,
resulting a
synergistic combination index of 0.47.
[0077] FIG. 44 is a dose-response curve showing effect of the neurogenic
agents azasetron
(5HT3 receptor antagonist) and ibudilast (PDE inhibitor) in combination on
neuronal
differentiation of human neural stem cells compared to the effect of either
agent alone. When
run independently, azasetron was tested in a concentration response curve
ranging from 0.01
uM to 31.6 uM, and ibudilast was tested in a response curve ranging from 0.003
- 10.0 uM.
In combination, the compounds were combined at a 1:3.16 ratio at each point
(for example,
the first point in the combined curve consisted of a test of 0.01 uM azasetron
and 0.003 uM
ibudilast). Data is presented as the percentage of the neuronal positive
control, with basal
CA 02726300 2010-12-22
media values subtracted. When used alone, EC50 was observed at an azasetron
concentration
of 5.8 uM or an ibudilast concentration of 0.72 uM in test cells. When used in
combination,
neurogenesis is greatly enhanced. EC50 was observed at a combination of
azasetron and
ibudilast at concentrations of 0.11 uM each, resulting a synergistic
combination index of
0.17.
100781 FIG. 45 is a dose-response curve showing effect of the neurogenic
agents azasetron
(5HT3 receptor antagonist) and naltrexone (mixed opioid antagonist) in
combination on
neuronal differentiation of human neural stem cells compared to the effect of
either agent
alone. When run independently, each compound was tested in a concentration
response
curve ranging from 0.01 uM to 31.6 uM. In combination, the compounds were
combined at
equal concentrations at each point (for example, the first point in the
combined curve
consisted of a test of 0.01 uM azasetron and 0.01 uM naltrexone). Data is
presented as the
percentage of the neuronal positive control, with basal media values
subtracted. When used
alone, EC50 was observed at an azasetron concentration of 5.8 uM or a
naltrexone
concentration of 0.39 uM in test cells. When used in combination, neurogenesis
is greatly
enhanced. EC50 was observed at a combination of azasetron and naltrexone at
concentrations
of 0.16 uM each, resulting a synergistic combination index of 0.45.
100791 FIG. 46 is a dose-response curve showing effect of the agents azasetron
(5HT3
receptor antagonist) and naltrexone (mixed opioid antagonist) in combination
on astrocyte
differentiation of human neural stem cells compared to the effect of either
agent alone. When
run independently, each compound was tested in a concentration response curve
ranging from
0.01 uM to 31.6 uM. In combination, the compounds were combined at equal
concentrations
at each point (for example, the first point in the combined curve consisted of
a test of 0.01
uM azasetron and 0.01 uM naltrexone). Data is presented as the percentage of
the neuronal
positive control, with basal media values subtracted. When used in combination
astrocyte
differentiation was reduced from a maximum of 33% with azasetron alone to a
maximum of
5% with the combination of azasetron and naltrexone.
[00801 FIG. 47 is a dose-response curve showing effect of the neurogenic
agents azasetron
(5HT3 receptor antagonist) and folic acid in combination on neuronal
differentiation of
human neural stem cells compared to the effect of either agent alone. When run
independently, each compound was tested in a concentration response curve
ranging from
0.01 uM to 31.6 uM. In combination, the compounds were combined at equal
concentrations
21
CA 02726300 2010-12-22
at each point (for example, the first point in the combined curve consisted of
a test of 0.01
uM azasetron and 0.01 uM folic acid). Data is presented as the percentage of
the neuronal
positive control, with basal media values subtracted. When used alone, EC50
was observed at
an azasetron concentration of 5.8 uM or a folic acid concentration of 4.5 uM
in test cells.
When used in combination, neurogenesis is greatly enhanced. EC50 was observed
at a
combination of azasetron and folic acid at concentrations of 0.19uM each,
resulting a
synergistic combination index of 0.08.
[00811 FIG. 48 is a dose-response curve showing effect of the agents azasetron
(5HT3
receptor antagonist) and folic acid in combination on astrocyte
differentiation of human
neural stem cells compared to the effect of either agent alone. When run
independently, each
compound was tested in a concentration response curve ranging from 0.01 uM to
31.6 uM.
In combination, the compounds were combined at equal concentrations at each
point (for
example, the first point in the combined curve consisted of a test of 0.01 uM
azasetron and
0.01 uM folic acid). Data is presented as the percentage of the neuronal
positive control, with
basal media values subtracted. When used in combination astrocyte
differentiation was
reduced from a maximum of 33% with azasetron alone to a maximum of 8% with the
combination of azasetron and folic acid.
100821 FIG. 49 is a dose-response curve showing effect of the neurogenic
agents azasetron
(5HT3 receptor antagonist) and gabapentin in combination on neuronal
differentiation of
human neural stem cells compared to the effect of either agent alone. When run
independently, each compound was tested in a concentration response curve
ranging from
0.01 uM to 31.6 uM. In combination, the compounds were combined at equal
concentrations
at each point (for example, the first point in the combined curve consisted of
a test of 0.01
uM azasetron and 0.01 uM gabapentin). Data is presented as the percentage of
the neuronal
positive control, with basal media values subtracted. When used alone, EC50
was observed at
an azasetron concentration of 5.8 uM or a gabapentin concentration of 11.5 uM
in test cells.
When used in combination, neurogenesis is greatly enhanced. EC50 was observed
at a
combination of azasetron and gabapentin at concentrations of 0.9 uM each,
resulting a
synergistic combination index of 0.24.
[00831 FIG. 50 is a dose-response curve showing effect of the neurogenic
agents azasetron
(5HT3 receptor antagonist) and methylphenidate (Ritalin ) in combination on
neuronal
differentiation of human neural stem cells compared to the effect of either
agent alone. When
22
CA 02726300 2010-12-22
run independently, azasetron was tested in a concentration response curve
ranging from 0.01
uM to 31.6 uM, and methylphenidate was tested in a response curve ranging from
0.003 -
10.0 uM. In combination, the compounds were combined at a 1:3.16 ratio at each
point (for
example, the first point in the combined curve consisted of a test of 0.01 uM
azasetron and
0.003 uM methylphenidate). Data is presented as the percentage of the neuronal
positive
control, with basal media values subtracted. When used alone, EC50 was
observed at an
azasetron concentration of 5.8 uM or a methylphenidate concentration of 2.2 uM
in test cells.
When used in combination, neurogenesis is greatly enhanced: EC50 was observed
at a
combination of azasetron and methylphenidate at concentrations of 0.09 uM
each, resulting a
synergistic combination index of 0.06.
100841 FIG. 51 is a dose-response curve showing effect of the agents azasetron
(5HT3
receptor antagonist) and methylphenidate (Ritalin(t) in combination on
astrocyte
differentiation of human neural stem cells compared to the effect of either
agent alone. When
run independently, azasetron was tested in a concentration response curve
ranging from 0.01
uM to 31.6 uM, and methylphenidate was tested in a response curve ranging from
0.003 -
10.0 uM. In combination, the compounds were combined at a 1:3.16 ratio at each
point (for
example, the first point in the combined curve consisted of a test of 0.01 uM
azasetron and
0.003 uM methylphenidate). Data is presented as the percentage of the neuronal
positive
control, with basal media values subtracted. When used in combination
astrocyte
differentiation was reduced from a maximum of 33% with azasetron alone to a
maximum of
4% with the combination of azasetron and methylphenidate.
100851 FIG. 52 is a dose-response curve showing effect of the neurogenic
agents azasetron
(5HT3 receptor antagonist) and clozapine in combination on neuronal
differentiation of
human neural stem cells compared to the effect of either agent alone. When run
independently, each compound was tested in a concentration response curve
ranging from
0.01 uM to 31.6 uM. In combination, the compounds were combined at equal
concentrations
at each point (for example, the first point in the combined curve consisted of
a test of 0.01
uM azasetron and 0.01 uM clozapine). Data is presented as the percentage of
the neuronal
positive control, with basal media values subtracted. When used alone, EC50
was observed at
an azasetron concentration of 5.8 uM or a clozapine concentration of 3.6 uM in
test cells.
When used in combination, neurogenesis is greatly enhanced: EC50 was observed
at a
23
CA 02726300 2010-12-22
combination of azasetron and clozapine at concentrations of 0.132 uM each,
resulting a
synergistic combination index of 0.06.
[0086] FIG. 53 is a dose-response curve showing effect of the neurogenic
agents azasetron
(5HT3 receptor antagonist) and carbemazepine in combination on neuronal
differentiation of
human neural stem cells compared to the effect of either agent alone. When run
independently, each compound was tested in a concentration response curve
ranging from
0.01 uM to 31.6 uM. In combination, the compounds were combined at equal
concentrations
at each point (for example, the first point in the combined curve consisted of
a test of 0.01
uM azasetron and 0.01 uM carbemazepine). Data is presented as the percentage
of the
neuronal positive control, with basal media values subtracted. When used
alone, EC50 was
observed at an azasetron concentration of 5.8 uM or a carbemazepine
concentration of 15.7
uM in test cells. When used in combination, neurogenesis is greatly enhanced.
EC50 was
observed at a combination of azasetron and carbemazepine at concentrations of
0.37 uM
each, resulting a synergistic combination index of 0.09.
[0087] FIG. 54 shows the effects of buspirone alone, melatonin alone, and the
combination of the two drugs on antidepressant activity in the novelty
suppressed feeding
assay with comparison to fluoxetine. Male F344 rats were dosed orally lx per
day for 21-
days with vehicle only (n = 12), 12.5 mg/kg fluoxetine (n = 12), 5 mg/kg
buspirone (n = 12),
1.0 mg/kg melatonin (n = 12), or the combination of the two drugs at the same
doses (n = 12).
Behavioral testing was carried out as described in Example 14. Results shown
in this figure
indicate the mean latency to approach and eat a food pellet within the novel
environment.
Data are presented as latency to eat a food pellet expressed in seconds (see
Examples 8 and
14). Melatonin or buspirone alone did not significantly reduce the latency to
eat the food
pellet but the melatonin and buspirone combination resulted in a significant
decrease in
latency. The data indicate that the combination of buspirone and melatonin at
doses that do
not produce antidepressant activity when dosed alone, result in significant
antidepressant
activity when administered in combination.
[0088] FIG. 55 shows additional studies of buspirone and melatonin alone and
in
combination in a novelty suppressed feeding assays (see Example 14 for
procedure) and in
vitro and in vivo analysis of neurogenesis. (A) In FIG. 55A Results of a
novelty suppressed
feeding (NSF) assay showing the latency to eat as a % of appropriate vehicle
control
24
CA 02726300 2010-12-22
(Latency, % Vehicle) in 8-10 week old male Fisher 344 rats from Harlan
(F344/NHsd).
Treatments were administered for 28 days either intraperitoneally (i.p.) at
doses indicated in
milligram per kilogram body weight (mpk). Vehicle was water for fluoxetine
(Flu) and
imipramine (Imi), and 3%Tween80 for buspirone (Bus). A reduction in the
latency to eat is
considered an antidepressant effect. The number of animals (n) for each
treatment group is
indicated. A p<0.05 indicates statistical significance based on an unpaired
two-tailed
Student's t-test comparing drug treatment versus appropriate vehicle control.
As seen in
Figure 55A, both fluoxetine and imipramine significantly reduced the latency
to eat while
buspirone at the low dose (0.5 mpk) showed a nonsignificant decrease compared
to the
respective vehicle controls. The higher dose of buspirone (5 mpk) induced an
increase in
latency to eat compared to its vehicle control. (B) Shown in Figure 55B are
the results of a
NSF assay showing latency to eat as a % of appropriate vehicle control
(Latency, % Vehicle).
Treatments were administered for 28 days by oral gavage (p.o.) at doses
indicated in
milligram per kilogram body weight (mpk). Vehicle was 3%Tween 80 for buspirone
alone
(Bus), melatonin (Mel) and the combination of buspirone and melatonin (Combo).
The
number of animals (n) is noted for each treatment group. A p<0.05 indicates
statistical
significance based on an unpaired two-tailed Student's t-test comparing drug
treatment versus
appropriate vehicle control. As shown, buspirone and melatonin when
administered as
monotherapies showed no effect on latency to eat. When administered in
combination, the
two dose combinations of buspirone + melatonin (5 and 10 mpk buspirone in
combination
with I mpk melatonin) significantly decreased the latency to eat (p=0.03 and
p=0.002
respectively). The combination having the higher dose of buspirone (10 mpk)
induced a
greater decrease in latency to eat. (C) Figure 55C shows the change in newborn
NSC counts
in the dentate gyrus as the total number of BrdU-positive cells per cubic mm
(BrdU+
Cells/mm3) as a % of appropriate vehicle control after 28 days of treatments
with fluoxetine
(Flu), imipramine (Imi), buspirone (Bus). The number of animals (n) is noted
for each
treatment group. Route and dose are as described for Figure 55A. A p<0.05
indicates
statistical significance based on an unpaired two-tailed Student's t-test
comparing drug
treatment versus appropriate vehicle control. As shown fluoxetine, imipramine
and the high
dose of buspirone (5 mpk) induced a significant increase in BrdU positive
cells compared to
the respective vehicle controls. The lower dose of buspirone (0.5 mpk)
produced a
nonsignificant increase. (D) Figure 55D shows the change in newborn NSC counts
in the
dentate gyrus as the total number of Ki-67-positive cells per cubic mm (Ki-67+
Cells/mm3) as
a % of appropriate vehicle control after 28 days of treatment with buspirone
alone (Bus),
CA 02726300 2010-12-22
melatonin alone (Mel), or the combination of buspirone and melatonin (Combo).
Treatments
were administered by oral gavage (p.o.) at doses indicated in milligram per
kilogram body
weight (mpk). The number of animals (n) is noted for each treatment group. A
p<0.05
indicates statistical significance based on an unpaired two-tailed Student's t-
test comparing
drug treatment versus appropriate vehicle control. As shown, neither buspirone
(10 pink) nor
melatonin (5 mpk) produced a significant increase to Ki-67-positive cells
while the
combination of the two agents resulted in a significant increase (p=0.002)
when compared to
the vehicle control.
100891 FIG. 56 shows the clinical trial CGI-I Rating data of patients with
Major
Depressive Disorder (MDD) treated with the Buspirone/melatonin combination.
(A) Figure
56A shows the CGI-I inherently measures a change from baseline. The scale
ranges from 1
to 7, with 7 indicating very much worse, 6 much worse, 5 minimally worse, 4 no
change, 3
minimally improved, 2 much improved and 1 very much improved. For the patients
that
completed 6 weeks of treatment, n=54 for the combination treatment group
("Combo"), n=30
for Placebo ("Placebo"), n=28 for buspirone alone ("Buspirone"). SEM indicates
standard
error of the mean. p values were calculated using an unpaired two tailed t-
test. The CGI-I
did not differ between the placebo and buspirone treated groups (p=0.786), and
as per the
statistical plan allowed the pooling of the placebo and buspirone alone
treated patients for
analyses. At 6 weeks there was a statistically significant improvement
comparing the
combination treatment versus placebo *p=0.043 or comparing the combination
treatment to
the pooled placebo and buspirone alone groups, +p=0.026. At 4 weeks there is a
trend to
efficacy versus placebo (p=0.079) and statistically significant improvement
compared to the
pooled placebo and buspirone alone groups #p=0.035. (B) Figure 56B shows the %
of
patients achieving a clinical response is shown for the various treatment
groups. X-axis
indicates Percent Responders defined as a CGI-I of <2. Combo indicates
combination
treatment, placebo, buspirone indicates buspirone alone. X2= 7.29, p<0.03
using a
contingency test.
[00901 Figures 57A, 57B, 58A, 58B, 59A and 59B show the individual dose
response
curves for the dose ranging and dose ratio studies for the following 5HT3
agents: azasetron
(Fig.57 A and B), granisetron (Fig.58 A and B) and ondansetron (Fig.59 A and
B) in
combination with naltrexone. For the ratios of 30:1, 10:1, 3:1, 1:1, and 1:3
(5HT3:naltrexone
ratio), the 5HT3 concentration ranged from 0.01 M to 31.6 gM for each dose
response
26
CA 02726300 2010-12-22
assay. The naltrexone concentrations were adjusted based on the respective
ratio. Due to
solubility issues for naltrexone, the 5HT3 concentration range for the 1:10
and 1:30 ratios
(5HT3:naltrexone ratio), were decreased to 0.001 M to 3.2 M for these dose
response
assays with the naltrexone concentration adjusted accordingly to the specified
ratio.
Individual dose response curves were prepared for each concentration ratio as
previously
described with cells stained with TUJ-1 antibody for the detection of neuronal
differentiation
or GFAP antibody for the detection of astrocyte differentiation (see Example
16). Analysis of
the azasetron + naltrexone combination showed synergy for inducing
neurogenesis at the
10:1, 3:1, 1:1, 1:3, 1:10 and 1:30 ratios and astrocyte suppression at the
30:1, 10:1, 3:1, 1:1,
1:3 and 1:10 ratios (Figures 57A and 57B). Analysis of the granisetron +
naltrexone
combination showed synergy for inducing neurogenesis at the 30:1, 10:1, 3:1,
1:1, 1:3, 1:10
and 1:30 ratios and astrocyte suppression at the 3:1, 1:1, 1:3 and 1:10 ratios
(Figures 58A and
58B). Analysis of the ondansetron + naltrexone combination showed synergy for
inducing
neurogenesis at the 30:1, 10:1, 3:1, 1:1, 1:3, and 1:30 ratios and astrocyte
suppression at the
30:1, 10:1, 3:1, 1:1, 1:3 and 1:10 ratios (Figures 59A and 59B).
[0091] FIG. 60 shows the effects of ondansetron alone, naltrexone alone, and
the
combination of the two drugs on antidepressant activity in the novelty
suppressed feeding
assay with comparison to imipramine. Male F344 rats were dosed
intraperitoneally (i.p.) lx
per day for 21-days with vehicle only (n = 10), 12.5 mg/kg imipramine (n =9),
3.33 mg/kg
ondansetron (n = 10), 1.0 mg/kg naltrexone (n = 9), or the combination of the
two drugs at
the same doses (n = 7) or combined at 1.0 mg/kg ondansetron with 0.3 mg/kg
naltrexone.
Behavioral testing was carried out as described in Example 14. Results shown
in this figure
indicate the mean latency to approach and eat a food pellet within the novel
environment.
Compared to vehicle control, animals treated with ondansetron + naltrexone
(3.33+1.0
mg/kg, i.p.) had a statistically significant decrease in latency to eat
(p<0.01, unpaired students
t-tests). Treatment for 28-day with naltrexone (1.0 mg/kg, i.p.) also resulted
in a statistically
significant decrease in latency to eat. (p<0.05, unpaired students t-tests).
Animals treated
with ondansetron + naltrexone at the lower dose (1.0 and 0.3 mg/kg, i.p.
respectively) had a
non-significant decrease in latency to eat (p=0.07, unpaired students t-
tests). The positive
control imipramine performed as expected and resulted in a statistically
significant decrease
in latency to eat (p<0.001, unpaired students t-tests). The data shows that a
synergistic effect
was achieved with the combination of ondansetron and naltrexone at the higher
dose
combination (3.33. and 1.0 mg/kg respectively) producing a reduction in
latency to eat
27
CA 02726300 2010-12-22
greater than the results achieved in combining the individual scores for the
drugs when used
as monotherapies.
DEFINITIONS
100921 "Neurogenesis" is defined herein as proliferation, differentiation,
migration and/or
survival of a neural cell in vivo or in vitro. In some embodiments, the neural
cell is an adult,
fetal, or embryonic neural stem cell or population of cells. The cells may be
located in the
central nervous system or elsewhere in an animal or human being. The cells may
also be in a
tissue, such as neural tissue. In some embodiments, the neural cell is an
adult, fetal, or
embryonic progenitor cell or population of cells, or a population of cells
comprising a
mixture of stem cells and progenitor cells. Neural cells include all brain
stem cells, all brain
progenitor cells, and all brain precursor cells. Neurogenesis includes
neurogenesis as it
occurs during normal development, as well as neural regeneration that occurs
following
disease, damage or therapeutic intervention, such as by the treatment
described herein.
100931 A "neurogenic agent" is defined as a chemical or biological agent or
reagent that
can promote, stimulate, or otherwise increase the amount or degree or nature
of neurogenesis
in vivo or ex vivo or in vitro relative to the amount, degree, or nature of
neurogenesis in the
absence of the agent or reagent. In some embodiments, treatment with a
neurogenic agent
increases neurogenesis if it promotes neurogenesis by at least about 5%, at
least about 10%,
at least about 25%, at least about 50%, at least about 100%, at least about
500%, or more in
comparison to the amount, degree, and/or nature of neurogenesis in the absence
of the agent,
under the conditions of the method used to detect or determine neurogenesis.
100941 The term "astrogenic" is defined in relation to "astrogenesis" which
refers to the
activation, proliferation, differentiation, migration and/or survival of an
astrocytic cell in vivo
or in vitro. Non-limiting examples of astrocytic cells include astrocytes,
activated microglial
cells, astrocyte precursors and potentiated cells, and astrocyte progenitor
and derived cells.
In some embodiments, the astrocyte is an adult, fetal, or embryonic astrocyte
or population of
astrocytes. The astrocytes may be located in the central nervous system or
elsewhere in an
animal or human being. The astrocytes may also be in a tissue, such as neural
tissue. In
some embodiments, the astrocyte is an adult, fetal, or embryonic progenitor
cell or population
of cells, or a population of cells comprising a mixture of stem and/or
progenitor cells, that
28
CA 02726300 2010-12-22
is/are capable of developing into astrocytes. Astrogenesis includes the
proliferation and/or
differentiation of astrocytes as it occurs during normal development, as well
as astrogenesis
that occurs following disease, damage or therapeutic intervention.
[00951 An "astrogenic agent" or an agent that is astrogenic is one that can
induce or
increase astrogenesis in a cell, a population of cells, or a tissue. In some
embodiments an
astrogenic agent may also be neurogenic. In particular embodiments, the
astrogenic agent
may be a 5HTR agent.
[00961 An "anti-astrogenic agent" is defined as a chemical agent or reagent
that can
inhibit, reduce, or otherwise decrease the amount or degree or nature of
astrogenesis in vivo,
ex vivo or in vitro relative to the amount, degree, or nature of astrogenesis
in the absence of
the anti-astrogenic agent or reagent. The antibody to glial fibrillary acidic
protein (GFAP)
may be used for the detection of astrocyte differentiation. In some
embodiments, treatment
with an anti-astrogenic agent decreases astrogenesis if it lowers astrocyte
production by at
least about 5%, at least about 10%, at least about 25%, at least about 50%, at
least about
100%, at least about 500%, or more in comparison to the amount, degree, and/or
nature of
astrogenesis in the absence of the anti-astrogenic agent, under the conditions
of the method
used to detect or determine astrogenesis. In certain embodiments, the anti-
astrogenic agent is
selected from the group consisting of a modulator of a melatonin receptor, a
GABA
modulator, an al adrenergic receptor modulator, an opioid agent, a
psychostimulant, a
norepinephrine and dopamine reuptake inhibitor, folic acid, and a folic acid
derivative.
Examples of each of these anti-astrogenic agents are provided below.
[0097) The term "stem cell" (or neural stem cell (NSC)), as used herein,
refers to an
undifferentiated cell that is capable of self-renewal and differentiation into
neurons,
astrocytes, and/or oligodendrocytes.
[00981 The term "progenitor cell" (e.g., neural progenitor cell), as used
herein, refers to a
cell derived from a stem cell that is not itself a stem cell. Some progenitor
cells can produce
progeny that are capable of differentiating into more than one cell type.
[00991 The terms "animal" or "animal subject" refers to a non-human mammal,
such as a
primate, canine, or feline. In other embodiments, the terms refer to an animal
that is
domesticated (e.g. livestock) or otherwise subject to human care and/or
maintenance (e.g. zoo
animals and other animals for exhibition). In other non-limiting examples, the
terms refer to
29
CA 02726300 2010-12-22
ruminants or carnivores, such as dogs, cats, birds, horses, cattle, sheep,
goats, marine animals
and mammals, penguins, deer, elk, and foxes.
[0100] The term "condition" refers to the physical and/or psychological state
of an animal
or human subject selected for treatment with the disclosed compound or
compounds. The
physical and/or psychological state of the animal or human subject at the time
of treatment
may include but is not limited to a disease state, a disease symptom, and /or
a disease
syndrome. The physical and/or psychological state of the animal or human
subject may be
the result of an injury, disease or disorder and/or a result of treating such
injury, disease or
disorder.
[0101] The term "nervous system disorder" refers to diseases and disorders of
the nervous
system categorized under "mental disorders" or "diseases and disorders of the
central nervous
system".
[0102] The term "mental disorder" refers to a group of disorders that are
commonly
associated with an anxiety disorder, a mood disorder or schizophrenia as
disclosed in
"Harrison's Principles of Internal Medicine" 17th edition, which is herein
incorporated in its
entirety.
[0103] The term "diseases and disorders of the central nervous system" include
but are not
limited to epilepsy, cerebrovascular disease, cognitive impairment,
neuropathy, myelopathy
and head injury as disclosed in "Harrison's Principles of Internal Medicine"
17'h edition,
which is incorporated in its entirety.
[0104] As used herein, the term "neurodegenerative disorder" encompasses
diseases and
disorders of the central nervous system wherein neuronal perturbations are the
result of the
disease or disorder. Non-limiting examples of neuronal perturbations are those
noted within
the hippocampus resulting in decreased neurogenesis, aberrant neurogenesis, as
well as
defects to neuronal and synaptic plasticity.
[0105] As used herein, the term "cognitive impairment" refers to diminished or
reduced
cognitive function. This may be the result of a number of natural and physical
events
including but not limited to aging, head trauma, diseases and disorders of the
central nervous
system, therapies related to treating a disease or disorder (drugs,
chemotherapy and radiation
therapy), as well as alcohol and drug abuse.
CA 02726300 2010-12-22
[01061 The terms "5HTR agent" and "5HTR compound" are used interchangeably
herein
and include a neurogenic agent, as defined herein, that elicits an observable
response upon
contacting a 5HT receptor, such as one or more of the subtypes described
herein. In other
embodiments, the 5HTR agent may be neurogenic and astrogenic. In still other
embodiments, the 5HTR agent may not be neurogenic or may not exibit neurogenic
properties in in vitro assays, but may be astrogenic. "5HTR agents" useful in
the methods
described herein include compounds or agents that, under certain conditions,
may act as:
agonists (i.e., agents able to elicit one or more biological responses of a
5HT receptor); partial
agonists (i.e., agents able to elicit one or more biological responses of a
5HT receptor to a
less than maximal extent, e.g., as defined by the response of the receptor to
an agonist);
antagonists (agents able to inhibit one or more characteristic responses of a
5HT receptor, for
example, by competitively or non-competitively binding to the 5HT receptor, a
ligand of the
receptor, and/or a downstream signaling molecule); and/or inverse agonists
(agents able to
block or inhibit a constitutive activity of a 5HT receptor) of one or more
subtypes of the 5HT
receptor. In some embodiments of the methods and compositions provided herein,
the 5HTR
agent is selected from the group consisting of a 5HT1a agonist, a 5HT3
antagonist, and a
5HT4 agonist.
[01071 In some embodiments, the 5HTR agent(s) used in the methods described
herein has
"selective" activity under certain conditions against one or more 5HT receptor
subtypes with
respect to the degree and/or nature of activity against one or more other 5HT
receptor
subtypes. For example, in some embodiments, the 5HTR agent has an agonist
effect against
one or more subtypes, and a much weaker effect or substantially no effect
against other
subtypes. As another example, a 5HTR agent used in the methods described
herein may act
as an agonist at one or more 5HT receptor subtypes and as antagonist at one or
more other
5HT receptor subtypes. In some embodiments, 5HTR agents have activity against
one 5HT
receptor subtype, while having substantially lesser activity against one or
more other 5HT
receptor subtypes. In certain embodiments, selective activity of one or more
5HT receptor
agonists, or antagonists, results in enhanced efficacy, fewer side effects,
lower effective
dosages, less frequent dosing, or other desirable attributes.
[01081 In some embodiments, the 5HTR agent(s) used in the compositions and
methods
described herein are substantially inactive with respect to other receptors
(i.e., non-5HT
receptor), such as muscarinic receptors, dopamine receptors, epinephrine
receptors, histamine
31
CA 02726300 2010-12-22
receptors, glutamate receptors, and the like. However, in other embodiments,
5HTR agent(s)
are active against one or more additional receptor subtypes. For example, the
reported 5HTR
agent, agomelatine, has antagonist properties with respect to 5-HT2B/2C
receptors and
agonist properties with respect to MT1 and MT2 melatonin receptors under
certain
conditions.
[0109] In additional embodiments, a 5HTR agent as used herein includes a
neurogenesis
modulating agent, as defined herein, that elicits an observable neurogenic
response by
producing, generating, stabilizing, or increasing the retention of an
intermediate agent which,
when contacted with a 5HT receptor agent, results in the neurogenic response.
As used
herein, "increasing the retention of' or variants of that phrase or the term
"retention" refer to
decreasing the degradation of, or increasing the stability of, an intermediate
agent.
[0110] In some cases, a 5HTR agent, in combination with one or more other
neurogenic
agents, or anti-astrogenic agent, results in improved efficacy, fewer side
effects, lower
effective dosages, less frequent dosing, and/or other desirable effects
relative to use of the
neurogenesis modulating agents individually (such as at higher doses), due,
e.g., to
synergistic activities and/or the targeting of molecules and/or activities
that are differentially
expressed in particular tissues and/or cell-types.
[0111] The term "neurogenic combination of a 5HTR agent with one or more other
neurogenic agents, or anti-astrogenic agent" refers to a combination of
neurogenesis
modulating agents. In some embodiments, administering a neurogenic, or
neuromodulating,
combination according to methods provided herein modulates neurogenesis in a
target tissue
and/or cell-type by at least about 20%, about 25%, about 30%, about 40%, about
50%, at
least about 75%, or at least about 90% or more in comparison to the absence of
the
combination. In further embodiments, neurogenesis is modulated by at least
about 95% or by
at least about 99% or more.
[0112] A neuromodulating combination may be used to inhibit a neural cell's
proliferation, division, or progress through the cell cycle. Alternatively, a
neuromodulating
combination may be used to stimulate survival and/or differentiation in a
neural cell. As an
additional alternative, a neuromodulating combination may be used to inhibit,
reduce, or
prevent astrocyte activation and/or astrogenesis or astrocyte differentiation.
32
CA 02726300 2010-12-22
[01131 "IC50" and "EC50" values are concentrations of an agent, in a
combination of a
5HTR agent with one or more other neurogenic agents, or anti-astrogenic agent,
that reduce
and promote, respectively, neurogenesis or another physiological activity
(e.g., the activity of
a receptor) to a half-maximal level. IC50 and EC50 values can be assayed in a
variety of
environments, including cell-free environments, cellular environments (e.g.,
cell culture
assays), multicellular environments (e.g., in tissues or other multicellular
structures), and/or
in vivo. In some embodiments, one or more neurogenesis modulating agents in a
combination or method disclosed herein individually have IC50 or EC50 values
of less than
about 10 M, less than about 1 M, or less than about 0.1 M or lower. In
other
embodiments, an agent in a combination has an IC50 or EC50 of less than about
50 nM, less
than about 10 nM, or less than about 1 nM, less than about 0.1 nM or lower.
[01141 In some embodiments, selectivity of one or more agents, in a
combination of a a
5HTR agent with one or more other neurogenic agents, or anti-astrogenic agent,
is
individually measured as the ratio of the IC50 or EC50 value for a desired
effect (e.g.,
modulation of neurogenesis) relative to the IC50/EC50 value for an undesired
effect. In some
embodiments, a "selective" agent in a combination has a selectivity of less
than about 1:2,
less than about 1:10, less than about 1:50, or less than about 1:100. In some
embodiments,
one or more agents in a combination individually exhibits selective activity
in one or more
organs, tissues, and/or cell types relative to another organ, tissue, and/or
cell type. For
example, in some embodiments, an agent in a combination selectively modulates
neurogenesis in a neurogenic region of the brain, such as the hippocampus
(e.g., the dentate
gyrus), the subventricular zone, and/or the olfactory bulb.
101151 In other embodiments, modulation by a combination of agents is in a
region
containing neural cells affected by disease or injury, region containing
neural cells associated
with disease effects or processes, or region containing neural cells affect
other event injurious
to neural cells. Non-limiting examples of such events include stroke or
radiation therapy of
the region. In additional embodiments, a neuromodulating combination
substantially
modulates two or more physiological activities or target molecules, while
being substantially
inactive against one or more other molecules and/or activities.
[01161 As used herein, the term "alkyl" as well as other groups having the
prefix "alk"
such as, for example, alkoxy, alkanoyl, alkenyl, alkynyl and the like, means
carbon chains
which may be linear or branched or combinations thereof. Examples of alkyl
groups include
33
CA 02726300 2010-12-22
methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl,
heptyl and the like.
Prefered alkyl groups have 1-8 carbons. "Alkenyl" and other like terms include
carbon
chains containing at least one unsaturated carbon-carbon bond. "Alkynyl" and
other like
terms include carbon chains containing at least one carbon-carbon triple bond.
[0117] As used herein, the term "cycloalkyl" means carbocycles containing no
heteroatoms, and includes mono-, bi- and tricyclic saturated carbocycles, as
well as fused ring
systems. Examples of cycloalkyl include but are not limited today cyclopropyl,
cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, decahydronaphthalene, adamantyl,
indanyl, indenyl,
fluorenyl, 1,2,3,4-tetrahydronaphthalene and the like.
[0118] As used herein, the term "aryl" means an aromatic substituent that is a
single ring
or multiple rings fused together. Exemplary aryl groups include, without
limitation, phenyl,
naphthyl, anthracenyl, pyridinyl, pyrazinyl, pyrimidinyl, triazinyl,
thiophenyl, furanyl,
pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, thioimidazolyl, oxazolyl,
isoxazolyl, triazyolyl,
and tetrazolyl groups. Aryl groups that contain one or more heteroatoms (e.g.,
pyridinyl) are
often referred to as "heteroaryl groups." When formed of multiple rings, at
least one of the
constituent rings is aromatic. In some embodiments, at least one of the
multiple rings contain
a heteroatom, thereby forming heteroatom-containing aryl groups. Heteroatom-
containing
aryl groups include, without limitation, benzoxazolyl, benzimidazolyl,
quinoxalinyl,
benzofuranyl, indolyl, indazolyl, benzimidazolyl, quinolinoyl, and I H-
benzo[d][1,2,3]triazolyl groups and the like. Heteroatom-containing aryl
groups also include
aromatic rings fused to a heterocyclic ring comprising at least one heteroatom
and at least one
carbonyl group. Such groups include, without limitation, dioxo
tetrahydroquinoxalinyl and
dioxo tetrahydroquinazolinyl groups.
[0119] As used herein, the term "arylalkoxy" means an aryl group bonded to an
alkoxy
group.
[0120] As used herein, the term "arylamidoalkyl" means an aryl-C(O)NR-alkyl or
aryl-
NRC(O)-alkyl.
[01211 As used herein, the term "arylalkylamidoalkyl" means an aryl-alkyl-
C(O)NR-alkyl
or aryl-alkyl-NRC(O)-alkyl, wherein R is any suitable group listed below.
34
CA 02726300 2010-12-22
[0122] As used herein, the term "arylalkyl" refers to an aryl group bonded to
an alkyl
group.
[0123] As used herein, the term "halogen" or "halo" refers to chlorine,
bromine, fluorine
or iodine.
[0124] As used herein, the term "haloalkyl" means an alkyl group having one or
more
halogen atoms (e.g., Triflouromethyl).
[0125] As used herein, the term "heteroalkyl" refers to an alkyl moiety which
comprises a
heteroatom such as N, 0, P, B, S, or Si. The heteroatom may be connected to
the rest of the
heteroalkyl moiety by a saturated or unsaturated bond. Thus, an alkyl
substituted with a
group, such as heterocycloalkyl, substituted heterocycloalkyl, heteroaryl,
substituted
heteroaryl, alkoxy, aryloxy, boryl, phosphino, amino, silyl, thio, or seleno,
is within the scope
of the term heteroalkyl. Examples of heteroalkyls include, but are not limited
to, cyano,
benzoyl, and substituted heteroaryl groups. For example, 2-pyridyl, 3-pyridyl,
4-pyridyl, and
2-furyl, 3-furyl, 4-furyl, 2-imidazolyl, 3-imidazolyl, 4-imidazolyl, 5-
imidazolyl.
[0126] As used herein, the term "heteroarylalkyl" means a heteroaryl group to
which an
alkyl group is attached.
[0127] As used herein, the term "heterocycle" means a monocyclic or polycyclic
ring
comprising carbon and hydrogen atoms, having 1, 2 or more multiple bonds, and
the ring
atoms contain at least one heteroatom, specifically 1 to 4 heteroatoms,
independently selected
from nitrogen, oxygen, and sulfur. Heterocycle ring structures include, but
are not limited to,
mono-, bi-, and tri-cyclic compounds. Specific heterocycles are monocyclic or
bicyclic.
Representative heterocycles include cyclic ureas, morpholinyl, pyrrolidinonyl,
pyrrolidinyl,
piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl,
tetrahydrofuranyl,
tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl,
tetrahydrothiophenyl,
tetrahydrothiopyranyl, tetrazolyl, azabicyclo[3.2.1]octanyl, hexahydro-lH-
quinolizinyl, and
urazolyl. A heterocyclic ring may be unsubstituted or substituted.
[0128] As used herein, the term "heterocycloalkyl" refers to a cycloalkyl
group in which
at least one of the carbon atoms in the ring is replaced by a heteroatom
(e.g., 0, S or N).
[0129] As used herein, the term "heterocycloalkylalkyl" means a
heterocycloalkyl group
to which the an alkyl group is attached.
CA 02726300 2010-12-22
[0130] As used herein, the term "substituted" specifically envisions and
allows for one or
more substitutions that are common in the art. However, it is generally
understood by those
skilled in the art that the substituents should be selected so as to not
adversely affect the
useful characteristics of the compound or adversely interfere with its
function. Suitable
substituents may include, for example, halogen groups, perfluoroalkyl groups,
perfluoroalkoxy groups, alkyl groups, alkenyl groups, alkynyl groups, hydroxy
groups, oxo
groups, mercapto groups, alkylthio groups, alkoxy groups, aryl or heteroaryl
groups, aryloxy
or heteroaryloxy groups, arylalkyl or heteroarylalkyl groups, arylalkoxy or
heteroarylalkoxy
groups, amino groups, alkyl- and dialkylamino groups, carbamoyl groups,
alkylcarbonyl
groups, carboxyl groups, alkoxycarbonyl groups, alkylaminocarbonyl groups,
dialkylamino
carbonyl groups, arylcarbonyl groups, aryloxycarbonyl groups, alkylsulfonyl
groups,
arylsulfonyl groups, cycloalkyl groups, cyano groups, CI-C6 alkylthio groups,
arylthio
groups, nitro groups, keto groups, acyl groups, boronate or boronyl groups,
phosphate or
phosphonyl groups, sulfamyl groups, sulfonyl groups, sulfinyl groups, and
combinations
thereof. In the case of substituted combinations, such as "substituted
arylalkyl," either the
aryl or the alkyl group may be substituted, or both the aryl and the alkyl
groups may be
substituted with one or more substituents. Additionally, in some cases,
suitable substituents
may combine to form one or more rings as known to those of skill in the art.
[0131] The compounds described herein may contain one or more double bonds and
may
thus give rise to cis/trans isomers as well as other conformational isomers.
The present
disclosure includes all such possible isomers as well as mixtures of such
"isomers".
[0132] The compounds described herein, and particularly the substituents
described
above, may also contain one or more asymmetric centers and may thus give rise
to
diastereomers and optical isomers. The present disclosure includes all such
possible
diastereomers as well as their racemic mixtures, their substantially pure
resolved
enantiomers, all possible geometric isomers, and acceptable salts thereof.
Further, mixtures
of stereoisomers as well as isolated specific stereoisomers are also included.
During the
course of the synthetic procedures used to prepare such compounds, or in using
racemization
or epimerization procedures known to those skilled in the art, the products of
such procedures
can be a mixture of stereoisomers.
[0133] As used herein, the term "salts" refer to derivatives of the disclosed
compounds
wherein the parent compound is modified by making acid or base salts thereof.
Examples of
36
CA 02726300 2010-12-22
pharmaceutically acceptable salts include, but are not limited to, mineral or
organic acid salts
of basic groups such as amines; and alkali or organic salts of acidic groups
such as carboxylic
acids. Pharmaceutically acceptable salts include the conventional non-toxic
salts or the
quaternary ammonium salts of the parent compound formed, for example, from non-
toxic
inorganic or organic acids. For example, such conventional non-toxic salts
include those
derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric with
replacement of
one or both protons, sulfamic, phosphoric with replacement of one or both
protons, e.g.
orthophosphoric, or metaphosphoric, or pyrophosphoric and nitric; and the
salts prepared
from organic acids such as acetic, propionic, succinic, glycolic, stearic,
lactic, malic, tartaric,
citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,
benzoic, salicylic,
sulfanilic, 2-acetoxybenzoic, embonic, nicotinic, isonicotinic and amino acid
salts, cyclamate
salts, fumaric, toluenesulfonic, methanesulfonic, N-substituted sulphamic,
ethane disulfonic,
oxalic, and isethionic, and the like. Also, such conventional non-toxic salts
include those
derived from inorganic acids such as non toxic metals derived from group Ia,
Ib, Ha and Ilb
in the periodic table. For example, lithium, sodium, or potassium magnesium,
calcium, zinc
salts, or ammonium salts such as those derived from mono, di and trialkyl
amines. For
example methyl-, ethyl-, diethyl, triethyl, ethanol, diethanol- or triethanol
amines or
quaternary ammonium hydroxides.
101341 The pharmaceutically acceptable salts of the present disclosure can be
synthesized
from the parent compound which contains a basic or acidic moiety by
conventional chemical
methods. Generally, such salts can be prepared by reacting the free acid or
base forms of
these compounds with a stoichiometric amount of the appropriate base or acid
in water or in
an organic solvent, or in a mixture of the two; generally, nonaqueous media
like ether, ethyl
acetate, ethanol, isopropanol, or acetonitrile. Lists of suitable salts are
found in Remington's
Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985,
p. 1418,
the disclosure of which is hereby incorporated by reference.
[01351 As used herein, the term "solvate" means a compound, or a salt thereof,
that further
includes a stoichiometric or non-stoichiometric amount of solvent bound by non-
covalent
intermolecular forces. Where the solvent is water, the solvate is a hydrate.
[0136] As used herein, the term "analog thereof' in the context of the
compounds
disclosed herein includes diastereomers, hydrates, solvates, salts, prodrugs,
and N-oxides of
the compounds.
37
CA 02726300 2010-12-22
[01371 As used herein, the term "Prodrug" in the context of the compounds
disclosed
herein includes alkoxycarbonyl, substituted alkoxycarbonyl, carbamoyl and
substituted
carbamoyl or a hydroxyl or other functionality that has been otherwise
modified by an
organic radical that can be removed under physiological conditions such that
the cleavage
products are physiologically tolerable at the resulting concentrations.
DETAILED DESCRIPTION OF MODES OF PRACTICING THE DISCLOSURE
General
101381 Methods described herein can be used to treat any disease or condition
for which it
is beneficial to promote or otherwise stimulate or increase neurogenesis. One
focus of the
methods described herein is to achieve a therapeutic result by stimulating or
increasing
neurogenesis via modulation of 5HT receptor activity. Thus, certain methods
described
herein can be used to treat any disease or condition susceptible to treatment
by increasing
neurogenesis.
[01391 In some embodiments, a disclosed method is applied to modulating
neurogenesis
in vivo, in vitro, or ex vivo. In in vivo embodiments, the cells may be
present in a tissue or
organ of a subject animal or human being. Non-limiting examples of cells
include those
capable of neurogenesis, such as to result, whether by differentiation or by a
combination of
differentiation and proliferation, in differentiated neural cells. As
described herein,
neurogenesis includes the differentiation of neural cells along different
potential lineages. In
some embodiments, the differentiation of neural stem or progenitor cells is
along a neuronal
cell lineage to produce neurons. In other embodiments, the differentiation is
along both
neuronal and glial cell lineages. In additional embodiments, the disclosure
further includes
differentiation along a neuronal cell lineage to the exclusion of one or more
cell types in a
glial cell lineage. Non-limiting examples of glial cell types include
oligodendrocytes and
radial glial cells, as well as astrocytes, which have been reported as being
of an "astroglial
lineage". Therefore, embodiments of the disclosure include differentiation
along a neuronal
cell lineage to the exclusion of one or more cell types selected from
oligodendrocytes, radial
glial cells, and astrocytes.
101401 In applications to an animal or human being, the disclosure includes a
method of
bringing cells into contact with a 5HTR agent, in combination with one or more
other
neurogenic agents, or anti-astrogenic agent, in effective amounts to result in
an increase in
neurogenesis in comparison to the absence of the agent or combination. A non-
limiting
38
CA 02726300 2010-12-22
example is in the administration of the agent or combination to the animal or
human being.
Such contacting or administration may also be described as exogenously
supplying the
combination to a cell or tissue.
[01411 Embodiments of the disclosure include a method to treat, or lessen the
level of, a
decline or impairment of cognitive function. Also included is a method to
treat a mood
disorder. In additional embodiments, a disease or condition treated with a
disclosed method
is associated with pain and/or addiction, but in contrast to known methods,
the disclosed
treatments are substantially mediated by increasing neurogenesis. As a further
non-limiting
example, a method described herein may involve increasing neurogenesis ex
vivo, such that a
composition containing neural stem cells, neural progenitor cells, and/or
differentiated neural
cells can subsequently be administered to an individual to treat a disease or
condition.
101421 In further embodiments, methods described herein allow treatment of
diseases
characterized by pain, addiction, and/or depression by directly replenishing,
replacing, and/or
supplementing neurons and/or glial cells. In further embodiments, methods
described herein
enhance the growth and/or survival of existing neural cells, and/or slow or
reverse the loss of
such cells in a neurodegenerative condition.
101431 Where a method comprises contacting a neural cell with a 5HTR agent,
the result
may be an increase in neurodifferentiation. The method may be used to
potentiate a neural
cell for proliferation, and thus neurogenesis, via the one or more other
agents used with the
5HTR agent in combination. Thus the disclosure includes a method of
maintaining,
stabilizing, stimulating, or increasing neurodifferentiation in a cell or
tissue by use of a 5HTR
agent, in combination with one or more other neurogenic agents, or anti-
astrogenic agent that
also increase neurodifferentiation. The method may comprise contacting a cell
or tissue with
a 5HTR agent, in combination with one or more other neurogenic agents, or anti-
astrogenic
agent, to maintain, stabilize, stimulate, or increase neurodifferentiation in
the cell or tissue.
101441 The disclosure also includes a method comprising contacting the cell or
tissue with
a 5HTR agent in combination with one or more other neurogenic agents, or anti-
astrogenic
agent where the combination stimulates or increases proliferation or cell
division in a neural
cell. The increase in neuroproliferation may be due to the one or more other
neurogenic
agents, or anti-astrogenic agent and/or to the 5HTR agent. In some cases, a
method
comprising such a combination may be used to produce neurogenesis (in this
case both
39
CA 02726300 2010-12-22
neurodifferentiation and/or proliferation) in a population of neural cells. In
some
embodiments, the cell or tissue is in an animal subject or a human patient as
described herein.
Non-limiting examples include a human patient treated with chemotherapy and/or
radiation,
or other therapy or condition which is detrimental to cognitive function; or a
human patient
diagnosed as having epilepsy, a condition associated with epilepsy, or
seizures associated
with epilepsy.
[01451 Administration of a 5HTR agent, in combination with one or more other
neurogenic agents, or anti-astrogenic agent, may be before, after, or
concurrent with, another
agent, condition, or therapy. In some embodiments, the overall combination may
be of a
5HTR agent, in combination with one or more other neurogenic agents, or anti-
astrogenic
agent.
Uses of a 5HTR agent
[01461 Embodiments include a method of modulating neurogenesis by contacting
one or
more neural cells with a 5HTR agent, in combination with one or more other
neurogenic
agents, or anti-astrogenic agent. The amount of a 5HTR agent, or a combination
thereof with
one or more other neurogenic agents, or anti-astrogenic agent, may be selected
to be effective
to produce an improvement in a treated subject, or detectable neurogenesis in
vitro. In some
embodiments, the amount is one that also minimizes clinical side effects seen
with
administration of the inhibitor to a subject.
Cognitive Function
101471 The term "cognitive function" refers to mental processes of an animal
or human
subject relating to information gathering and/or processing; the
understanding, reasoning,
and/or application of information and/or ideas; the abstraction or
specification of ideas and/or
information; acts of creativity, problem-solving, and possibly intuition; and
mental processes
such as learning, perception, and/or awareness of ideas and/or information.
The mental
processes are distinct from those of beliefs, desires, and the like. In some
embodiments,
cognitive function may be assessed, and thus defined, via one or more tests or
assays for
cognitive function. Non-limiting examples of a test or assay for cognitive
function include
CANTAB (see for example Fray et al. "CANTAB battery: proposed utility in
neurotoxicology." Neurotoxicol Teratol. 1996; 18(4):499-504), Stroop Test,
Trail Making,
Wechsler Digit Span, or the CogState computerized cognitive test (see also
Dehaene et al.
"Reward-dependent learning in neuronal networks for planning and decision
making." Prog
CA 02726300 2010-12-22
Brain Res. 2000;126:217-29; Iverson et al. "Interpreting change on the WAIS-
III/WMS-III in
clinical samples." Arch Clin Neuropsychol. 2001;16(2):183-91; and Weaver et
al. "Mild
memory impairment in healthy older adults is distinct from normal aging."
Brain Cogn.
2006;60(2):146-55).
[0148] In other embodiments, and if compared to a reduced level of cognitive
function, a
method of the invention may be for enhancing or improving the reduced
cognitive function in
a subject or patient. The method may comprise administering a 5HTR agent, in
combination
with one or more other neurogenic agents, or anti-astrogenic agent, to a
subject or patient to
enhance, or improve a decline or decrease, of cognitive function due to a
therapy and/or
condition that reduces cognitive function. Other methods of the disclosure
include treatment
to affect or maintain the cognitive function of a subject or patient. In some
embodiments, the
maintenance or stabilization of cognitive function may be at a level, or
thereabouts, present in
a subject or patient in the absence of a therapy and/or condition that reduces
cognitive
function. In alternative embodiments, the maintenance or stabilization may be
at a level, or
thereabouts, present in a subject or patient as a result of a therapy and/or
condition that
reduces cognitive function.
[0149] In further embodiments, and if compared to a reduced level of cognitive
function
due to a therapy and/or condition that reduces cognitive function, a method of
the invention
may be for enhancing or improving the reduced cognitive function in a subject
or patient.
The method may comprise administering a 5HTR agent, or a combination thereof
with one or
more other neurogenic agents, or anti-astrogenic agent, to a subject or
patient to enhance or
improve a decline or decrease of cognitive function due to the therapy or
condition. The
administering may be in combination with the therapy or condition.
[0150] These methods optionally include assessing or measuring cognitive
function of the
subject or patient before, during, and/or after administration of the
treatment to detect or
determine the effect thereof on cognitive function. So in one embodiment, a
methods may
comprise i) treating a subject or patient that has been previously assessed
for cognitive
function and ii) reassessing cognitive function in the subject or patient
during or after the
course of treatment. The assessment may measure cognitive function for
comparison to a
control or standard value (or range) in subjects or patients in the absence of
a 5HTR agent, or
a combination thereof with one or more other neurogenic agents, or anti-
astrogenic agent.
41
CA 02726300 2010-12-22
This maybe used to assess the efficacy of the 5HTR agent, alone or in a
combination, in
alleviating the reduction in cognitive function.
Mood disorders
101511 The term "mood disorder" is typically characterized by pervasive,
prolonged, and
disabling exaggerations of mood, which are associated with behavioral,
physiologic,
cognitive, neurochemical and psychomotor dysfunctions. As used herein a mood
disorder
includes but is not limited to bipolar disorders, depression including major
depressive
disorder (MDD), and depression associated with various disease states and
injuries.
Representative and non-limiting mood disorders are described herein including
depression,
anxiety, hypomania, panic attacks, excessive elation, seasonal mood (or
affective) disorder,
schizophrenia and other psychoses, lissencephaly syndrome, anxiety syndromes,
anxiety
disorders, phobias, stress and related syndromes, aggression, non-senile
dementia, post-pain
depression, and combinations thereof. Efficacy instruments used for depression
include CGI-
Severity (CGI-S), Inventory of Depressive Symptoms (IDS-c30), QIDS-SR16 and
the
Hamilton Depression Scale (Ham-D) (Rush et al, Biol Psychiatry 54:573-83,
2003; Guy,
ECDEU Assessment Manual for Psychopharmacology (revised) 193-198; Rush et al.,
Psychol Med 26:477-86, 1996; and Hamilton, Br J Med Psychol 32:50-5).
[01521 In other embodiments, a disclosed method may be used to moderate or
alleviate a
mood disorder in a subject or patient as described herein. Thus the disclosure
includes a
method of treating a mood disorder in such a subject or patient. Non-limiting
examples of
the method include those comprising administering a 5HTR agent, or a
combination thereof
with one or more other neurogenic agents, or anti-astrogenic agent, to a
subject or patient that
is under treatment with a therapy and/or condition that results in a mood
disorder. The
administration may be with any combination and/or amount that is effective to
produce an
improvement in the mood disorder.
Identification of Subjects and Patients
[01531 The disclosure includes methods comprising identification of an
individual
suffering from one or more disease, disorders, or conditions, or a symptom
thereof, and
administering to the subject or patient a 5HTR agent, in combination with one
or more other
neurogenic agents, or anti-astrogenic agent, as described herein. The
identification of a
subject or patient as having one or more disease, disorder or condition, or a
symptom thereof,
may be made by a skilled practitioner using any appropriate means known in the
field.
42
CA 02726300 2010-12-22
[0154] In some embodiments, identification of a patient in need of
neurogenesis
modulation comprises identifying a patient who has or will be exposed to a
factor or
condition known to inhibit neurogenesis, including but not limited to, stress,
aging, sleep
deprivation, hormonal changes (e.g., those associated with puberty, pregnancy,
or aging (e.g.,
menopause), lack of exercise, lack of environmental stimuli (e.g., social
isolation), diabetes
and drugs of abuse (e.g., alcohol, especially chronic use; opiates and
opioids;
psychostimulants). In some cases, the patient has been identified as non-
responsive to
treatment with primary medications for the condition(s) targeted for treatment
(e.g., non-
responsive to antidepressants for the treatment of depression), and a 5HTR
agent, in
combination with one or more other neurogenic agents, or anti-astrogenic
agent, is
administered in a method for enhancing the responsiveness of the patient to a
co-existing or
pre-existing treatment regimen.
[0155] In other embodiments, the method or treatment comprises administering a
combination of a primary medication or therapy for the condition(s) targeted
for treatment
and a 5HTR agent, in combination with one or more other neurogenic agents, or
anti-
astrogenic agent. For example, in the treatment of depression or related
neuropsychiatric
disorders, a combination may be administered in conjunction with, or in
addition to,
electroconvulsive shock treatment, a monoamine oxidase modulator, and/or a
selective
reuptake modulators of serotonin and/or norepinephrine.
[0156] In additional embodiments, the patient in need of neurogenesis
modulation suffers
from premenstrual syndrome, post-partum depression, or pregnancy-related
fatigue and/or
depression, and the treatment comprises administering a therapeutically
effective amount of a
5HTR agent, in combination with one or more other neurogenic agents, or anti-
astrogenic
agent. Without being bound by any particular theory, and offered to improve
understanding
of the invention, it is believed that levels of steroid hormones, such as
estrogen, are increased
during the menstrual cycle during and following pregnancy, and that such
hormones can exert
a modulatory effect on neurogenesis.
[0157] In some embodiments, the patient is a user of a recreational drug
including, but not
limited to, alcohol, amphetamines, PCP, cocaine, and opiates. Without being
bound by any
particular theory, and offered to improve understanding of the invention, it
is believed that
some drugs of abuse have a modulatory effect on neurogenesis, which is
associated with an
affective disorder (depression and/or anxiety) and other mood disorders, as
well as deficits in
43
CA 02726300 2010-12-22
cognition, learning, and memory. Moreover, mood disorders are causative/risk
factors for
substance abuse, and substance abuse is a common behavioral symptom (e.g.,
self
medicating) of mood disorders. Thus, substance abuse and mood disorders may
reinforce
each other, rendering patients suffering from both conditions non-responsive
to treatment.
Thus, in some embodiments, a 5HTR agent, in combination with one or more other
neurogenic agents, or anti-astrogenic agent, to treat patients suffering from
substance abuse
and/or mood disorders. In additional embodiments, the 5HTR agent, in
combination with one
or more other neurogenic agents, or anti-astrogenic agent, can used in
combination with one
or more additional agents selected from an antidepressant, an antipsychotic, a
mood
stabilizer, or any other agent known to treat one or more symptoms exhibited
by the patient.
In some embodiments, a 5HTR agent exerts a synergistic effect with the one or
more
additional agents in the treatment of substance abuse and/or mood disorders in
patients
suffering from both conditions.
[0158] In further embodiments, the patient is on a co-existing and/or pre-
existing
treatment regimen involving administration of one or more prescription
medications having a
modulatory effect on neurogenesis. For example, in some embodiments, the
patient suffers
from chronic pain and is prescribed one or more opiate/opioid medications;
and/or suffers
from ADD, ADHD, or a related disorder, and is prescribed a psychostimulant,
such as
Ritalin , dexedrine, adderall, or a similar medication which inhibits
neurogenesis. Without
being bound by any particular theory, and offered to improve understanding of
the invention,
it is believed that such medications can exert a modulatory effect on
neurogenesis, leading to
an affective disorder (depression and anxiety) and other mood disorders, as
well as deficits in
cognition, learning, and memory. Thus, in some preferred embodiments, a 5HTR
agent, in
combination with one or more other neurogenic agents, or anti-astrogenic
agent, is
administered to a patient who is currently or has recently been prescribed a
medication that
exerts a modulatory effect on neurogenesis, in order to treat the affective
disorder (depression
and/or anxiety), and/or other mood disorders, and/or to improve cognition.
[0159] In additional embodiments, the patient suffers from chronic fatigue
syndrome; a
sleep disorder; lack of exercise (e.g., elderly, infirm, or physically
handicapped patients);
and/or lack of environmental stimuli (e.g., social isolation); and the
treatment comprises
administering a therapeutically effective amount of a 5HTR agent, in
combination with one
or more other neurogenic agents, or anti-astrogenic agent.
44
CA 02726300 2010-12-22
[01601 In more embodiments, the patient is an individual having, or who is
likely to
develop, a disorder relating to neural degeneration, neural damage and/or
neural
demyelination.
101611 In further embodiments, a subject or patient includes human beings and
animals in
assays for behavior linked to neurogenesis. Exemplary human and animal assays
are known
to the skilled person in the field.
[01621 In yet additional embodiments, identifying a patient in need of
neurogenesis
modulation comprises selecting a population or sub-population of patients, or
an individual
patient, that is more amenable to treatment and/or less susceptible to side
effects than other
patients having the same disease or condition. In some embodiments,
identifying a patient
amenable to treatment with a 5HTR agent, in combination with one or more other
neurogenic
agents, or anti-astrogenic agent, comprises identifying a patient who has been
exposed to a
factor known to enhance neurogenesis, including but not limited to, exercise,
hormones or
other endogenous factors, and drugs taken as part of a pre-existing treatment
regimen. In
some embodiments, a sub-population of patients is identified as being more
amenable to
neurogenesis modulation with a 5HTR agent, in combination with one or more
other
neurogenic agents, or anti-astrogenic agent, by taking a cell or tissue sample
from prospective
patients, isolating and culturing neural cells from the sample, and
determining the effect of
the combination on the degree or nature of neurogenesis of the cells, thereby
allowing
selection of patients for which the therapeutic agent has a substantial effect
on neurogenesis.
Advantageously, the selection of a patient or population of patients in need
of or amenable to
treatment with a 5HTR agent, in combination with one or more other neurogenic
agents, or
anti-astrogenic agent, of the disclosure allows more effective treatment of
the disease or
condition targeted for treatment than known methods using the same or similar
compounds.
[01631 In some embodiments, the patient has suffered a CNS insult, such as a
CNS lesion,
a seizure (e.g., electroconvulsive seizure treatment; epileptic seizures),
radiation,
chemotherapy and/or stroke or other ischemic injury. Without being bound by
any particular
theory, and offered to improve understanding of the invention, it is believed
that some CNS
insults/injuries leads to increased proliferation of neural stem cells, but
that the resulting
neural cells form aberrant connections which can lead to impaired CNS function
and/or
diseases, such as temporal lobe epilepsy. In other embodiments, a 5HTR agent,
in
combination with one or more other neurogenic agents, or anti-astrogenic
agent, is
CA 02726300 2010-12-22
administered to a patient who has suffered, or is at risk of suffering, a CNS
insult or injury to
stimulate neurogenesis. Advantageously, stimulation of the differentiation of
neural stem
cells with a 5HTR agent, in combination with one or more other neurogenic
agents, or anti-
astrogenic agent, activates signaling pathways necessary for progenitor cells
to effectively
migrate and incorporate into existing neural networks or to block
inappropriate proliferation.
Opiate or Opioid Based Analgesic
[0164] Additionally, the disclosed methods provide for the application of a
5HTR agent,
in combination with one or more other neurogenic agents, or anti-astrogenic
agent, to treat a
subject or patient for a condition due to the anti-neurogenic effects of an
opiate or opioid
based analgesic. In some embodiments, the administration of an opiate or
opioid based
analgesic, such as an opiate like morphine or other opioid receptor agonist,
to a subject or
patient results in a decrease in, or inhibition of, neurogenesis. The
administration of a 5HTR
agent, in combination with one or more other neurogenic agents, or anti-
astrogenic agent,
with an opiate or opioid based analgesic would reduce the anti-neurogenic
effect. One non-
limiting example is administration of such a combination with an opioid
receptor agonist
after surgery (such as for the treating post-operative pain).
[0165] Also the disclosed embodiments include a method of treating post
operative pain in
a subject or patient by combining administration of an opiate or opioid based
analgesic with a
5HTR agent, in combination with one or more other neurogenic agents, or anti-
astrogenic
agent. The analgesic may have been administered before, simultaneously with,
or after the
combination. In some cases, the analgesic or opioid receptor agonist is
morphine or another
opiate.
[0166] Other disclosed embodiments include a method to treat or prevent
decreases in, or
inhibition of, neurogenesis in other cases involving use of an opioid receptor
agonist. The
methods comprise the administration of a 5HTR agent, in combination with one
or more
other neurogenic agents, or anti-astrogenic agent, as described herein. Non-
limiting
examples include cases involving an opioid receptor agonist, which decreases
or inhibits
neurogenesis, and drug addiction, drug rehabilitation, and/or prevention of
relapse into
addiction. In some embodiments, the opioid receptor agonist is morphine, opium
or another
opiate.
46
CA 02726300 2010-12-22
[01671 In further embodiments, the disclosure includes methods to treat a
cell, tissue, or
subject which is exhibiting decreased neurogenesis or increased
neurodegeneration. In some
cases, the cell, tissue, or subject is, or has been, subjected to, or
contacted with, an agent that
decreases or inhibits neurogenesis. One non-limiting example is a human
subject that has
been administered morphine or other agent which decreases or inhibits
neurogenesis. Non-
limiting examples of other agents include opiates and opioid receptor
agonists, such as mu
receptor subtype agonists, that inhibit or decrease neurogenesis.
101681 Thus in additional embodiments, the methods may be used to treat
subjects having,
or diagnosed with, depression or other withdrawal symptoms from morphine or
other agents
which decrease or inhibit neurogenesis. This is distinct from the treatment of
subjects
having, or diagnosed with, depression independent of an opiate, such as that
of a psychiatric
nature, as disclosed herein. In further embodiments, the methods may be used
to treat a
subject with one or more chemical addiction or dependency, such as with
morphine or other
opiates, where the addiction or dependency is ameliorated or alleviated by an
increase in
neurogenesis.
Transplantation
101691 In other embodiments, methods described herein involve modulating
neurogenesis
in vitro or ex vivo with a 5HTR agent, in combination with one or more other
neurogenic
agents, or anti-astrogenic agent, such that a composition containing neural
stem cells, neural
progenitor cells, and/or differentiated neural cells can subsequently be
administered to an
individual to treat a disease or condition. In some embodiments, the method of
treatment
comprises the steps of contacting a neural stem cell or progenitor cell with a
5HTR agent, in
combination with one or more other neurogenic agents, or anti-astrogenic
agent, to modulate
neurogenesis, and transplanting the cells into a patient in need of treatment.
Methods for
transplanting stem and progenitor cells are known in the art, and are
described, e.g., in U.S.
Patent Nos. 5,928,947; 5,817,773; and 5,800,539, and PCT Publication Nos. WO
01/176507
and WO 01/170243, all of which are incorporated herein by reference in their
entirety. In
some embodiments, methods described herein allow treatment of diseases or
conditions by
directly replenishing, replacing, and/or supplementing damaged or
dysfunctional neurons. In
further embodiments, methods described herein enhance the growth and/or
survival of
existing neural cells, and/or slow or reverse the loss of such cells in a
neurodegenerative or
other condition.
47
CA 02726300 2010-12-22
101701 In alternative embodiments, the method of treatment comprises
identifying,
generating, and/or propagating neural cells in vitro or ex vivo in contact
with a 5HTR agent,
in combination with one or more other neurogenic agents, or anti-astrogenic
agent, and
transplanting the cells into a subject. In another embodiment, the method of
treatment
comprises the steps of contacting a neural stem cell of progenitor cell with a
5HTR agent, in
combination with one or more other neurogenic agents, or anti-astrogenic
agent, to stimulate
neurogenesis or neurodifferentiation, and transplanting the cells into a
patient in need of
treatment. Also disclosed are methods for preparing a population of neural
stem cells
suitable for transplantation, comprising culturing a population of neural stem
cells (NSCs) in
vitro, and contacting the cultured neural stem cells with a 5HTR agent, in
combination with
one or more other neurogenic agents, or anti-astrogenic agent, as described
herein. The
disclosure further includes methods of treating the diseases, disorders, and
conditions
described herein by transplanting such treated cells into a subject or
patient.
Neurogenesis with Angiogenesis
101711 In additional embodiments, the disclosure includes a method of
stimulating or
increasing neurogenesis in a subject or patient with stimulation of
angiogenesis in the subject
or patient. The co-stimulation may be used to provide the differentiating
and/or proliferating
cells with increased access to the circulatory system. The neurogenesis is
produced by
modulation of 5HT receptor activity, such as with a 5HTR agent, in combination
with one or
more other neurogenic agents, or anti-astrogenic agent, as described herein.
An increase in
angiogenesis may be mediated by a means known to the skilled person, including
administration of a angiogenic factor or treatment with an angiogenic therapy.
Non-limiting
examples of angiogenic factors or conditions include vascular endothelial
growth factor
(VEGF), angiopoietin-1 or -2, erythropoietin, exercise, or a combination
thereof.
[01721 So in some embodiments, the disclosure includes a method comprising
administering i) a 5HTR agent, in combination with one or more other
neurogenic agents, or
anti-astrogenic agent, and ii) one or more angiogenic factors to a subject or
patient. In other
embodiments, the disclosure includes a method comprising administering i) a
5HTR agent, in
combination with one or more other neurogenic agents, or anti-astrogenic
agent, to a subject
or patient with ii) treating said subject or patient with one or more
angiogenic conditions.
The subject or patient may be any as described herein.
48
CA 02726300 2010-12-22
[0173] The co-treatment of a subject or patient includes simultaneous
treatment or
sequential treatment as non-limiting examples. In cases of sequential
treatment, the
administration of a 5HTR agent, with one or more other neurogenic agents, or
anti-astrogenic
agent, may be before or after the administration of an angiogenic factor or
condition. Of
course in the case of a combination of a 5HTR agent and one or more other
neurogenic
agents, or anti-astrogenic agent, the 5HTR agent may be administered
separately from the
one or more other agents, such that the one or more other agent is
administered before or after
administration of an angiogenic factor or condition.
Additional Diseases and Conditions
[0174] As described herein, the disclosed embodiments include methods of
treating
diseases, disorders, and conditions of the central and/or peripheral nervous
systems (CNS and
PNS, respectively) by administering a 5HTR agent, in combination with one or
more other
neurogenic agents, or anti-astrogenic agent. As used herein, "treating"
includes prevention,
amelioration, alleviation, and/or elimination of the disease, disorder, or
condition being
treated or one or more symptoms of the disease, disorder, or condition being
treated, as well
as improvement in the overall well being of a patient, as measured by
objective and/or
subjective criteria. In some embodiments, treating is used for reversing,
attenuating,
minimizing, suppressing, or halting undesirable or deleterious effects of, or
effects from the
progression of, a disease, disorder, or condition of the central and/or
peripheral nervous
systems. In other embodiments, the method of treating may be advantageously
used in cases
where additional neurogenesis would replace, replenish, or increase the
numbers of cells lost
due to injury or disease as non-limiting examples.
[0175] The amount of a 5HTR agent, in combination with one or more other
neurogenic
agents, or anti-astrogenic agent may be any that results in a measurable
relief of a disease
condition like those described herein. As a non-limiting example, an
improvement in the
Hamilton depression scale (HAM-D) score for depression may be used to
determine (such as
quantitatively) or detect (such as qualitatively) a measurable level of
improvement in the
depression of a subject.
[0176] Non-limiting examples of symptoms that may be treated with the methods
described herein include abnormal behavior, abnormal movement, hyperactivity,
hallucinations, acute delusions, combativeness, hostility, negativism,
withdrawal, seclusion,
memory defects, sensory defects, cognitive defects, and tension. Non-limiting
examples of
49
CA 02726300 2010-12-22
abnormal behavior include irritability, poor impulse control, distractibility,
and
aggressiveness. Outcomes from treatment with the disclosed methods include
improvements
in cognitive function or capability in comparison to the absence of treatment.
10177] Additional examples of diseases and conditions treatable by the methods
described
herein include, but are not limited to, neurodegenerative disorders and neural
disease, such as
dementias (e.g., senile dementia, memory disturbances/memory loss, dementias
caused by
neurodegenerative disorders (e.g., Alzheimer's, Parkinson's disease,
Parkinson's disorders,
Huntington's disease (Huntington's Chorea), Lou Gehrig's disease, multiple
sclerosis, Pick's
disease, Parkinsonism dementia syndrome), progressive subcortical gliosis,
progressive
supranuclear palsy, thalmic degeneration syndrome, hereditary aphasia,
amyotrophic lateral
sclerosis, Shy-Drager syndrome, and Lewy body disease; vascular conditions
(e.g., infarcts,
hemorrhage, cardiac disorders); mixed vascular and Alzheimer's; bacterial
meningitis;
Creutzfeld-Jacob Disease; and Cushing's disease).
101781 The disclosed embodiments also provide for the treatment of a nervous
system
disorder related to neural damage, cellular degeneration, a psychiatric
condition, cellular
(neurological) trauma and/or injury (e.g., subdural hematoma or traumatic
brain injury), toxic
chemicals (e.g., heavy metals, alcohol, some medications), CNS hypoxia, or
other
neurologically related conditions. In practice, the disclosed compositions and
methods may
be applied to a subject or patient afflicted with, or diagnosed with, one or
more central or
peripheral nervous system disorders in any combination. Diagnosis may be
performed by a
skilled person in the applicable fields using known and routine methodologies
which identify
and/or distinguish these nervous system disorders from other conditions.
101791 Non-limiting examples of nervous system disorders related to cellular
degeneration
include neurodegenerative disorders, neural stem cell disorders, neural
progenitor cell
disorders, degenerative diseases of the retina, and ischemic disorders. In
some embodiments,
an ischemic disorder comprises an insufficiency, or lack, of oxygen or
angiogenesis, and non-
limiting example include spinal ischemia, ischemic stroke, cerebral
infarction, multi-infarct
dementia. While these conditions may be present individually in a subject or
patient, the
disclosed methods also provide for the treatment of a subject or patient
afflicted with, or
diagnosed with, more than one of these conditions in any combination.
CA 02726300 2010-12-22
[0180] Non-limiting embodiments of nervous system disorders related to a
psychiatric
condition include neuropsychiatric disorders and affective disorders. As used
herein, an
affective disorder refers to a disorder of mood such as, but not limited to,
depression, anxiety,
post-traumatic stress disorder (PTSD), hypomania, panic attacks, excessive
elation, bipolar
depression, bipolar disorder (manic-depression), and seasonal mood (or
affective) disorder.
In some embodiments, an affective disorder is depression and/or anxiety. A
subject or patient
afflicted with an affective disorder may exhibit the symptoms of depression
and/or anxiety.
Agents that may be used to treat anxiety or depression (e.g. anxiolytics and
antidepressants)
may be identified using the novelty suppressed feeding assay, as an in vivo
model for anxiety
and/or depression.
[0181] The term "anxiety disorder" refers to or connotes significant distress
and
dysfunction due to feelings of apprehension, guilt, fear, and the like.
Anxiety disorders
include, but are not limited to panic disorders, posttraumatic stress
disorder, obsessive-
compulsive disorder and phobic disorders. The Hamilton Anxiety Scale (Ham-A)
is an
instrument used to measure the efficacy of drugs or procedures for treating
anxiety
(Hamilton, Br J Med Psychol 32:50-5).
[0182] Examples of nervous system disorders related to cellular or tissue
trauma and/or
injury include, but are not limited to, neurological traumas and injuries,
surgery related
trauma and/or injury, retinal injury and trauma, injury related to epilepsy,
cord injury, spinal
cord injury, brain injury, brain surgery, trauma related brain injury, trauma
related to spinal
cord injury, brain injury related to cancer treatment, spinal cord injury
related to cancer
treatment, brain injury related to infection, brain injury related to
inflammation, spinal cord
injury related to infection, spinal cord injury related to inflammation, brain
injury related to
environmental toxin, and spinal cord injury related to environmental toxin.
[0183] Non-limiting examples of nervous system disorders related to other
neurologically
related conditions include learning disorders, memory disorders, age-
associated memory
impairment (AAMI) or age-related memory loss, autism, learning or attention
deficit
disorders (ADD or attention deficit hyperactivity disorder, ADHD), narcolepsy,
sleep
disorders and sleep deprivation (e.g., insomnia, chronic fatigue syndrome),
cognitive
disorders, epilepsy, injury related to epilepsy, and temporal lobe epilepsy.
51
CA 02726300 2010-12-22
101841 Other non-limiting examples of diseases and conditions treatable by the
methods
described herein include, but are not limited to, hormonal changes (e.g.,
depression and other
mood disorders associated with puberty, pregnancy, or aging (e.g.,
menopause)); and lack of
exercise (e.g., depression or other mental disorders in elderly, paralyzed, or
physically
handicapped patients); infections (e.g., HIV); genetic abnormalities (down
syndrome);
metabolic abnormalities (e.g., vitamin B12 or folate deficiency);
hydrocephalus; memory loss
separate from dementia, including mild cognitive impairment (MCI), age-related
cognitive
decline, and memory loss resulting from the use of general anesthetics,
chemotherapy,
radiation treatment, post-surgical trauma, or therapeutic intervention; and
diseases of the of
the peripheral nervous system (PNS), including but not limited to, PNS
neuropathies (e.g.,
vascular neuropathies, diabetic neuropathies, amyloid neuropathies, and the
like), neuralgias,
neoplasms, myelin-related diseases, etc.
101851 Other conditions that can be beneficially treated by increasing
neurogenesis are
known in the art (see e.g., U.S. Publication Nos. 20020106731, 2005/0009742
and
2005/0009847, 20050032702, 2005/0031538, 2005/0004046, 2004/0254152,
2004/0229291,
and 2004/0185429, herein incorporated by reference in their entirety).
5HTR agents
101861 A 5HTR agent can be is a ligand which modulates activity at one or more
5HT
receptor subtypes. In some cases, the ligand may bind or interact with one or
more subtypes.
In other cases, the ligand may modulate activity indirectly as described
herein. In some
embodiments, the agent is an agonist of one or more subtypes. In other
embodiments, the
agent is an antagonist of one or more subtypes. In additional embodiments, the
agent is an
agonist of at least one subtype as well as an antagonist of at least one other
subtype.
[01871 A 5HT receptor agent for use in embodiments of the invention includes a
reported
5HT1a receptor agonist (or partial agonist) such as buspirone hydrochloride
(BuSpar ). In
some embodiments, a reported 5HT 1 a receptor agonist is an azapirone, such
as, but not
limited to, tandospirone, gepirone and ipsapirone. Non-limiting examples of
additional
reported 5HTIa receptor agonists include flesinoxan(CAS RN 98206-10-1), MDL
72832
hydrochloride, U-92016A, (+)-UH 301, F 13714, F 13640, 6-hydroxy-buspirone
(see US
2005/0137206), S-6-hydroxy-buspirone (see US 2003/0022899), R-6-hydroxy-
buspirone (see
US 2003/0009851), adatanserin, buspirone-saccharide (see WO 00/12067) or 8-
hydroxy-2-
dipropylaminotetralin (8-OHDPAT).
52
CA 02726300 2010-12-22
[0188] Additional non-limiting examples of reported 5HTIa receptor agonists
include
OPC-14523 (1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-methoxy-3,4-
dihydro-2[1H]-
quinolinone monomethanesulfonate); BMS-181100 or BMY 14802 (CAS RN 105565-56-
8);
flibanserin (CAS RN 167933-07-5); repinotan (CAS RN 144980-29-0); lesopitron
(CAS RN
132449-46-8); piclozotan (CAS RN 182415-09-4); aripiprazole, Org-13011 (1-(4-
trifluoromethyl-2-pyridinyl)-4- [4-[2-oxo-l-pyrrolidinyl]butyl]piperazine (E)-
2-
butenedioate); SDZ-MAR-327 (see Christian et al. "Positron emission
tomographic analysis
of central dopamine D1 receptor binding in normal subjects treated with the
atypical
neuroleptic, SDZ MAR 327." Int J Mol Med. 1998 1(l):243-7); MKC-242 ((S)-5-[3-
[(1,4-
benzodioxan-2-ylmethyl)amino]propoxy]-1,3-benzodioxole HC1); vilazodone;
sarizotan
(CAS RN 177975-08-5); roxindole (CAS RN 112192-04-8) or roxindole
methanesulfonate
(CAS RN 119742-13-1); alnespirone (CAS RN 138298-79-0); bromerguride (CAS RN
83455-48-5); xaliproden (CAS RN 135354-02-8); mazapertine succinate (CAS RN
134208-
18-7) or mazapertine (CAS RN 134208-17-6); PRX-00023; F-13640 ((3-chloro-4-
fluoro-
phenyl)-[4-fluoro-4-[[(5-methyl-pyridin-2-ylmethyl)-amino]methyl]piperidin- I -
yl]methanone, fumaric acid salt); eptapirone (CAS RN 179756-85-5); ziprasidone
(CAS RN
146939-27-7); sunepitron (see Becker et al. "G protein-coupled receptors: In
silico drug
discovery in 3D" PNAS 2004 101(31):11304-11309); umespirone (CAS RN 107736-98-
1);
SLV-308; bifeprunox; and zalospirone (CAS RN 114298-18-9).
[0189] Yet further non-limiting examples include AP-521 (partial agonist from
AsahiKasei) and Du-123015 (from Solvay).
[0190] It is a specific object of the invention to provide 5HT1 a agonists
which can be
represented by the following formulae.
[0191] In a first aspect, a compound of structural Formula (I) is provided:
R2
A--(CH X-(CH2C-B
or a salt, hydrate, solvate or N-oxide thereof or a derivative thereof which
is a prodrug
wherein:
A and B are independently selected from the group consisting of hydrogen,
alkyl
substituted alkyl, alkenyl, substituted alkenyl, alkynyl substituted alkynyl,
alkoxy, substituted
53
CA 02726300 2010-12-22
alkoxy, alkylthio, substituted alkylthio, alkylaryl, substituted alkylaryl,
alkoxyaryl,
substituted alkoxyaryl, aryl, substituted aryl, aryloxy, substituted aryloxy,
heteroaryl,
substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroalkyl,
substituted
heteroalkyl, OR3, S(O)bR3, NR3R4, SO2NR3R4, NR'SO2R4, NR3SO2NR4R5;
n is 0 or an integer selected from 1 - 5
X is selected from CH2, S(O)b, NR3 or O.
m is 0 or an integer selected from 1 - 5
R' and R2 are independently selected from the group consisting of hydrogen,
halogen,
hydroxy, cyano, carboxy,Ci-C8 alkyl, substituted C1-C8 alkyl, alkenyl,
substituted alkenyl,
alkynyl substituted alkynyl, aryl, substituted aryl, heteroalkyl, substituted
heteroalkyl,
heteroaryl, substituted heteroaryl, OR3, S(O)bR3, NR3R4;
b = 0,1, or 2
R3-R5 are independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,
heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,
substituted
heteroarylalkyl, Acylamido , substituted acylamido, diacylamido, substituted
diacylamido or
alternatively, R3 and R4, R3 and R5, or R4 and R5, together with the atoms to
which they are
bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
[0192] A preferred embodiment of the invention provides compounds having
structural
Formula (I) shown above or a salt, hydrate, solvate or N-oxide thereof or a
derivative thereof
which is a prodrug wherein:
A and B are independently selected from the group consisting of hydrogen,
alkyl
substituted alkyl, alkenyl, substituted alkenyl, alkynyl substituted alkynyl,
alkoxy, substituted
alkoxy, alkylthio, substituted alkylthio, alkylaryl, substituted alkylaryl,
alkoxyaryl,
substituted alkoxyaryl, aryl, substituted aryl, aryloxy, substituted aryloxy,
heteroaryl,
substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroalkyl,
substituted
heteroalkyl, OR3, S(O)bR3, NR3R4;
nis0or1-4
X is selected from CH2, or NR3.
m is 0, 1 or 2
R' and R2 are independently selected from the group consisting of hydrogen,
halogen,
hydroxy, cyano, carboxy,Ci-C8 alkyl, substituted C1-C8 alkyl, alkenyl,
substituted alkenyl,
54
CA 02726300 2010-12-22
alkynyl substituted alkynyl, aryl, substituted aryl, heteroalkyl, substituted
heteroalkyl,
heteroaryl, substituted heteroaryl, OR3, S(O)bR3, NR3R4;
b=0,l,or2
R3-R4 are independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,
heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,
substituted
heteroarylalkyl, Acylamido , substituted acylamido, diacylamido, substituted
diacylamido or
alternatively, R3 and R4, together with the atoms to which they are bonded
form a
cycloheteroalkyl or substituted cycloheteroalkyl ring;
[01931 A more preferred embodiment of the invention provides compounds having
structural Formula (I) shown above or a salt, hydrate, solvate or N oxide
thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (a) below;
O
N
R6
R7 O
(a)
Where R6and R7 are independently selected from the group consisting of
hydrogen,
C1-C4 alkyl, substituted C1-C4 alkyl, or alternatively, R6 and R7 together
with the atoms to
which they are bonded form a cycloalkyl or cycloheteroalkyl ring;
B is selected from the group consisting of alkyl substituted alkyl, alkenyl,
substituted
alkenyl, alkynyl substituted alkynyl, alkoxy, substituted alkoxy, alkylthio,
substituted
alkylthio, alkylaryl, substituted alkylaryl, alkoxyaryl, substituted
alkoxyaryl, aryl, substituted
aryl, aryloxy, substituted aryloxy, heteroaryl, substituted heteroaryl,
heteroaryloxy,
substituted heteroaryloxy, heteroalkyl, substituted heteroalkyl, OR3, S(O)bR3,
NR3R4;
n is 0 or 1 -4
X is selected from CH2, or NR3.
mis0,1or2
R1 and R2 are independently selected from the group consisting of hydrogen,
halogen,
hydroxy, cyano, carboxy,C1-C8 alkyl, substituted C1-Cg alkyl, OR3, NR3R4;
R3-R4 are independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,
heteroalkyl,
CA 02726300 2010-12-22
substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,
substituted
heteroarylalkyl, Acylamido , substituted acylamido, diacylamido, substituted
diacylamido or
alternatively, R3 and R4 together with the atoms to which they are bonded form
a
cycloheteroalkyl or substituted cycloheteroalkyl ring; Where R6and R7 are
independently
selected from the group consisting of hydrogen, CI-C4 alkyl, substituted C1-C4
alkyl, or
alternatively, R6 and R7 together with the atoms to which they are bonded form
a cycloalkyl
or cycloheteroalkyl ring;
[01941 An even more preferred embodiment of the invention provides compounds
having
structural Formula (I) shown above or a salt, hydrate, solvate or N oxide
thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (a) below;
O
N
R6
R7 O
(a)
Where R6and R7 are independently selected from the group consisting of
hydrogen,
Ci-C4 alkyl, substituted C1-C4 alkyl, or alternatively, R6 and R7 together
with the atoms to
which they are bonded form a cycloalkyl or cycloheteroalkyl ring;
B is of the formula (b) below;
s
r N' R
NJ
(b)
Where R8 is selected from the group consisting of aryl, substituted aryl,
heteroaryl,
substituted heteroaryl, heteroalkyl and substituted heteroalkyl,
n is 0, or 1 -4
X is selected from CH2, or NR6.
m is 0, 1 or 2
R' and R2 are independently selected from the group consisting of hydrogen,
halogen,
hydroxy, C1-C3 alkyl, substituted C1-C3 alkyl, OR3;
R3 is independently selected from the group consisting of hydrogen, C1-C3
alkyl,
substituted C1-C3 alkyl.
56
CA 02726300 2010-12-22
101951 An especially preferred embodiment of the invention provides compounds
having
structural Formula (I) shown above or a salt, hydrate, solvate or N oxide
thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (a) below;
O
N
R6
R7
(a)
Where R6 and R7 are independently selected from the group consisting of
hydrogen,
C1-C4 alkyl, or alternatively, R6 and R7 together with the atoms to which they
are bonded
form a cycloalkyl or cycloheteroalkyl ring;
B is of the formula (b) below;
R8
NJ
(b)
Where R8 is of the formula (c) or (d) below;
(R9)o
N
(c)
(R9)o
`ZZZ N
(d)
Where W and Y are independently selected from either N or CH and
Each R9 is independently selected from Hydrogen, halogen, C1-C3 alkyl, or
triflouromethyl and o is 0 or an integer from 1-3;
nis0, 1 or2
XisCH2.
m is 0, 1 or 2
57
CA 02726300 2010-12-22
R' and R2 are independently selected from the group consisting of hydrogen,
halogen,
hydroxy, C1-C3 alkyl, substituted C1-C3 alkyl, OR3;
R3 is independently selected from the group consisting of hydrogen, C1-C3
alkyl,
substituted C1-C3 alkyl.
[01961 An even more especially preferred embodiment of the invention provides
compounds having the following structures. or a salt, hydrate, solvate, N
oxide, or a
derivative thereof which is a prodrug wherein:
O O 0C N
O N `-J N-K\ `) O N N~\ `J
N N
O O
N N
j N N-
0C 0C
O N N \ / O N N--/\\ N N
O O
N
O N N \ \-J N
N
0
N
0 O
NN~ O' N -- K O ON I ~~ N-
0 ~JN~\ '
N
O O
N N
D
58
CA 02726300 2010-12-22
O
O
N
N O N N--/\\ NK N O \ N-\ :/~-F
O N
N
K I
O N N-{\ OH
N
10197] Another especially preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (a) below;
O
N
R6 _f~
R7
(a)
Where R6 and R7 are independently selected from the group consisting of
hydrogen,
C I -C4 alkyl, or alternatively, R6 and R7 together with the atoms to which
they are bonded
form a cycloalkyl or cycloheteroalkyl ring;
B is of the formula (b) below;
s
r N' R
NJ
(b)
Where R8 is of the formula (e) below;
N
(O)q
(e)
Where g is 0, 1, or 2
n and in are both 1
X is CH2i
R' and R2 are hydrogen;
59
CA 02726300 2010-12-22
[01981 An even more especially preferred embodiment of the invention provides
compounds having the following structures. or a salt, hydrate, solvate, N
oxide, or a
derivative thereof which is a prodrug wherein:
0 0 0
Q( N /-1 N- S N
N-
>C Q( O~NN S O~N N S O~N N ~S
[01991 Another especially preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (a) below;
O
N
R6 -f~
R7
(a)
Where R6 and R7 are independently selected from the group consisting of
hydrogen,
C 1-C4 alkyl, or alternatively, R6 and R7 together with the atoms to which
they are bonded
form a cycloalkyl or cycloheteroalkyl ring;
B is of the formula (f) below;
O R11
(R10) p Ny
(fl
Each R10 is independently selected from Hydrogen, halogen, C1-C4 alkyl,
hydroxyl,
azido, CN, NO2, OR6, NR6R' , C02R6, CO NR6R7 where R6 and R7 are as described
above
and p is 0 or an integer from 1-4
R" is selected from Hydrogen, or C1-C3 alkyl;
nis0or1
X is selected from CH2;
mis0or1
R1 and R2 are hydrogen;
CA 02726300 2010-12-22
[02001 Another even more especially preferred embodiment of the invention
provides
compounds having the following structures. or a salt, hydrate, solvate, N
oxide, or a
derivative thereof which is a prodrug wherein:
0 0 0
O ,,, ~N I j O ~~ I jo N 0
N O N /_j /
0 O O_N -O
O O
H 0 I'~
C)( N O/ N ^
Y`Oi`,%
O NH O
[02011 Another especially preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (a) below;
O
N
R6
R7
(a)
Where R6 and R7 are independently selected from the group consisting of
hydrogen,
CI-C4 alkyl, or alternatively, R6 and R7 together with the atoms to which they
are bonded
form a cycloalkyl or cycloheteroalkyl ring;
B is of the formula (g) below;
R13
~~
(R12)
M--0
P (g)
Each R12 is independently selected from Hydrogen, halogen, C1-C4 alkyl,
hydroxyl,
azido, CN, NO2, OR6, NR6R7 , C02R6, CO NR6R7 where R6 and R7 are as described
above
and p is 0 or an integer from 1-4
R13 is selected from Hydrogen, or C1-C3 alkyl;
n and m are both 1
X is CH2;
61
CA 02726300 2010-12-22
R' and R2 are hydrogen;
102021 Another even more especially preferred embodiment of the invention
provides
compounds having the following structures. or a salt, hydrate, solvate, N
oxide, or a
derivative thereof which is a prodrug wherein:
o O o
N )0 N )a N <
~~N~O ~N~O ~NJ O
-O -O O
O O O
N N ~N
O N~O N-/ O
-O -O
[02031 Another more preferred embodiment of the invention provides compounds
having
structural Formula (I) shown above or a salt, hydrate, solvate or N oxide
thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (h) below;
0
(R12)p N-1
~O)r
(h)
Each R12 is independently selected from Hydrogen, halogen, C1-C4 alkyl,
hydroxyl,
azido, CN, NO2, OR6, NR6R7 , C02R6, CO NR6R7 where R6 and R7 are as described
above
and p is 0 or an integer from 1-4
Ris0, 1, or2
n is 0, 1 or 2
X is CH2,
m is 0, 1 or 2
R1 and R2 are independently selected from the group consisting of hydrogen,
halogen,
hydroxy, cyano, carboxy,C1-C3 alkyl, substituted C1-C3 alkyl, OR3, NR3R4;
R3-R4 are independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,
heteroalkyl,
62
CA 02726300 2010-12-22
substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,
substituted
heteroarylalkyl, Acylamido, substituted acylamido, diacylamido, substituted
diacylamido or
alternatively, R3 and R4 together with the atoms to which they are bonded form
a
cycloheteroalkyl or substituted cycloheteroalkyl ring;
B is of the formula (b) above and R8 is of the formula (c) or (d) above;
Where W and Y are independently selected from either N or CH and
Each R9 is independently selected from Hydrogen, halogen, C1-C3 alkyl, or
triflouromethyl and o is 0 or an integer from 1-3;
[02041 Another especially preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (h) below;
0
(R12)p N-~
)r
(h)
R'2 is selected from Hydrogen and halogen and p is 1
ris2
n is 0 or 1
X is CH2,
mis0or1
R' and R2 are hydrogen,
B is of the formula (b) above and R8 is of the formula (c) or (d) above;
Where W and Y are independently selected from either N or CH and
Each R9 is independently selected from Hydrogen, halogen, C1-C3 alkyl, or
triflouromethyl and o is 0 or an integer from 1-3;
102051 Another even more especially preferred embodiment of the invention
provides
compounds having the following structures. or a salt, hydrate, solvate, N
oxide, or a
derivative thereof which is a prodrug wherein:
63
CA 02726300 2010-12-22
/-\ N- N-
N
O CI O
N- ~--~ N~j
F O ~-~N \N) ON~N F
{
00 00
N N-
F 0 CN - 0 ~j N---\ CI
N
{ ,
00 0
-S 'S
ON N--~ A O~N N
F \ N N
N { , N
-s -S
00 0
[02061 Another more preferred embodiment of the invention provides compounds
having
structural Formula (I) shown above or a salt, hydrate, solvate or N oxide
thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (h) below;
0
(R12)p ,N-1
(0)r
(h)
Each R' 2 is independently selected from Hydrogen, halogen, Ci-C4 alkyl,
hydroxyl,
azido, CN, NO2, OR6, NR6R7 , C02R6, CO NR6R7 where R6 and R7 are as described
above
and p is 0 or an integer from 1-4
Ris0, 1,or2
n is 0, 1 or 2
X is CH2,
mis0, 1 or2
R1 and R2 are independently selected from the group consisting of hydrogen,
halogen,
hydroxy, cyano, carboxy,Ci-C3 alkyl, substituted C1-C3 alkyl, OR3, NR3R4;
R3-R4 are independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,
heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,
substituted
heteroarylalkyl, Acylamido , substituted acylamido, diacylamido, substituted
diacylamido or
64
CA 02726300 2010-12-22
alternatively, R3 and R4 together with the atoms to which they are bonded form
a
cycloheteroalkyl or substituted cycloheteroalkyl ring;
B is of the formula (f) above where
Each R10 is independently selected from Hydrogen, halogen, CI-C4 alkyl,
hydroxyl,
azido, CN, NO2, OR6, NR6R7 , C02R6, CO NR6R7 where R6 and R7 are as described
above
and p is 0 or an integer from 1-4
R" is selected from Hydrogen, or CI-C3 alkyl;
[0207] Another especially preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (h) below;
0
(R12)p N-1
S
(0)r
(h)
R'2 is selected from Hydrogen and halogen and p is 1
r is 2
nis0orl
X is CH2,
mis0or1
R' and R2 are hydrogen,
B is of the formula (f) above where
R'0 is selected from Hydrogen or halogen and p is 0 or I
R" is selected from Hydrogen, or CI-C3 alkyl;
[0208] Another even more especially preferred embodiment of the invention
provides
compounds having the following structures. or a salt, hydrate, solvate, N-
oxide, or a
derivative thereof which is a prodrug wherein:
CA 02726300 2010-12-22
r z
0
0 / NH V.,,,. 0 j a N ~.. _ a
`ma y ff r .., r? /
N-
;fA
{_) 00 0 / NH ,t) 0
F.,,` /-:
LY N-' N-'
0 {) 0
:.~ j-
U NH 0 0 , - N 0
\N- N-,
0 0
0-c .!, {)
0 NH _0 0 _N ;_.... 6
Nom N-
O
[02091 Another preferred embodiment of the invention provides compounds having
structural Formula (I) shown above or a salt, hydrate, solvate or N oxide
thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (i) below;
R, 130
R14
N-1
R15
0
(i)
R13, R14, and R15 are independently selected from the group consisting of
hydrogen,
alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, or
alternatively, R'3 and R14, or
R14 and R15 together with the atoms to which they are bonded form a
cycloalkyl, substituted
cycloalkyl cycloheteroalkyl or substituted cycloheteroalkyl ring;
66
CA 02726300 2010-12-22
B are independently selected from the group consisting of hydrogen, alkyl
substituted
alkyl, alkenyl, substituted alkenyl, alkynyl substituted alkynyl, alkoxy,
substituted alkoxy,
alkylthio, substituted alkylthio, alkylaryl, substituted alkylaryl,
alkoxyaryl, substituted
alkoxyaryl, aryl, substituted aryl, aryloxy, substituted aryloxy, heteroaryl,
substituted
heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroalkyl, substituted
heteroalkyl,
OR3, S(O)bR3, NR3R4;
nis0or1-4
X is selected from CH2, or NR3.
in is 0, 1 or 2
R' and R2 are independently selected from the group consisting of hydrogen,
halogen,
hydroxy, cyano, carboxy,C1-C8 alkyl, substituted C1-Cg alkyl, alkenyl,
substituted alkenyl,
alkynyl substituted alkynyl, aryl, substituted aryl, heteroalkyl, substituted
heteroalkyl,
heteroaryl, substituted heteroaryl, OR3, S(O)bR3, NR3R4;
b=0,1,or2
R3-R4 are independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,
heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,
substituted
heteroarylalkyl, Acylamido , substituted acylamido, diacylamido, substituted
diacylamido or
alternatively, R3 and R4, together with the atoms to which they are bonded
form a
cycloheteroalkyl or substituted cycloheteroalkyl ring;
[02101 Another more preferred embodiment of the invention provides compounds
having
structural Formula (I) shown above or a salt, hydrate, solvate or N-oxide
thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (i) above where;
R13, Rio, and R15 are independently selected from the group consisting of
hydrogen,
alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, or
alternatively, R13 and R14, or
R14 and R15 together with the atoms to which they are bonded form a
cycloalkyl, substituted
cycloalkyl cycloheteroalkyl or substituted cycloheteroalkyl ring;
B are independently selected from the group consisting of aryl, substituted
aryl,
heteroaryl, substituted heteroaryl,
nis0orl
X is CH2.
in is I or2
67
CA 02726300 2010-12-22
R' and R2 are hydrogen
[02111 Another even more preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (i) above where;
R13, R14, and R15 are independently selected from the group consisting of
hydrogen,
alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, or
alternatively, R13 and R14, or
R14 and R15 together with the atoms to which they are bonded form a
cycloalkyl, substituted
cycloalkyl cycloheteroalkyl or substituted cycloheteroalkyl ring;
B is of the formula (b) above
And R8 is either aryl, substituted aryl,
nis0orl
X is CH2.
m is 1 or 2
R' and R2 are hydrogen
[02121 Another even more preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (i) above where;
R13, R14, and R15 are independently selected from the group consisting of
hydrogen,
alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, or
alternatively, R13 and R14, or
R14 and R15 together with the atoms to which they are bonded form a
cycloalkyl, substituted
cycloalkyl cycloheteroalkyl or substituted cycloheteroalkyl ring;
B is of the formula (b) above
And R8 is of the formula (c), (d) above where
Where W and Y are independently selected from either N or CH and
Each R9 is independently selected from Hydrogen, halogen, C1-C3 alkyl, or
triflouromethyl and o is 0 or an integer from 1-3;
nis0orl
X is CH2.
mis I or 2
R1 and R2 are hydrogen
68
CA 02726300 2010-12-22
102131 Another even more preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (i) above where;
Ri3, R14, and R15 are independently selected from the group consisting of
hydrogen,
alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, or
alternatively, R13 and R'4, or
R14 and R15 together with the atoms to which they are bonded form a
cycloalkyl, substituted
cycloalkyl cycloheteroalkyl or substituted cycloheteroalkyl ring;
B is of the formula (b) above
And R 8 is of the formula (e) above where;
Where g is 0, 1, or 2 and
nis0or1
X is CH2.
mis 1 or2
R' and R2 are hydrogen
[02141 Another especially preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is selected from one of the radicals below:
0 0
N- [i N-1
0 0 0
0 0
0
H 0 _ irk ;'~
N-j
0
N U I
H , c 0
H H 0 H H 0 H H1 0H H 0 H H t~ H H 0
69
CA 02726300 2010-12-22
0 H 0 0 O
N-~ N-j N-~ N-1
EC C (D
0 0 0 O
0 0 \,N_& 0
,N-&
O O N 0 O N 0 0
and
B are independently selected from the group consisting of aryl, substituted
aryl,
heteroaryl, substituted heteroaryl,
nis0or1
X is CH2.
m is 1 or 2
R1 and R2 are hydrogen
[02151 Another especially preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is selected from one of the radicals below:
0 0 0
r "0
H C)
N ~ N-jN- N- N J ~t r
H 0 0 0
CA 02726300 2010-12-22
H O H O H H O H H 0
N-1 N-1
N-~ N-~
EO
H O H 0 0 Fi H O
0 H 0 0 0
N-1 N-1 N-~ N-1
EC C
0 Fi 0 0 0
And B is of the formula (b) above
And R8 is either aryl, substituted aryl,
nis0orI
XisCH2.
in is I or 2
R1 and R2 are hydrogen
102161 Another especially preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is selected from one of the radicals below:
0 0 0
O
N I N- C N-~
0 0 0 0
O 0
H 0 O O
C N-j N-~ N-j N-1 N_~
O O
H 0 O O
H O H 0 H H 0 H H 0
N- N-~ N-1 I N-
H 0 Fi 0 Fi H- 0 Fi H- 0
71
CA 02726300 2010-12-22
0 H 0 0 O
N-1 N-~ N-j N-j
EC <z - (I
0 H 0 0 O
and B is of the formula (b) above
And R8 is of the formula (c), (d) above where
Where W and Y are independently selected from either N or CH and
Each R9 is independently selected from Hydrogen, halogen, CI-C3 alkyl, or
triflouromethyl and o is 0 or an integer from 1-3;
n is 0 or I
X is CH2.
mis 1 or2
R' and R2 are hydrogen
102171 Another especially preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is selected from one of the radicals below:
O O O
O
N- N-j N-j
O O O O
O O
H 0 O O
N-f N-~ N-1 0 I N-j
N-
0 O
0 O O
H O H 0 H H 0 H H 0
N-~ N-~ N-j
H O Fi 0 0 0
72
CA 02726300 2010-12-22
O H 0 O O
E() N-~ N-~ C N-j N-~
O O O O
and B is of the formula (b) above
And R8 is of the formula (e) above where;
Where g is 0, 1, or 2 and
nis0or1
XisCH2.
mislor2
R' and R2 are hydrogen
[02181 Another even more especially preferred embodiment of the invention
provides
compounds having the following structures. or a salt, hydrate, solvate, N-
oxide, or a
derivative thereof which is a prodrug:
N 11, O CI N4 O O
~N\ / O N rN \ /
O 0 N--\-,\_ N~ O
\,NJL 0 N--& O 0
CI
O O N~N O O N--\--\, r'N \ --\~N,__j Nj
N 0 0 --\,N-& 0 0
O O N N\/ O O N'-\--\_ f'N\/
N\___j
--W- --~N~ 0 O
^ CI
N1,
0 O ~~ / N\ 0 O N rN \
N\__j N\__j
73
CA 02726300 2010-12-22
t, ~.. N
N_._, r
N
h CJ
0
-N
N
N N N-
a
CF3 0 C`"F
"0 0
N
N
* N N cl N N
NN
r ^~ `4 N. N N' "' I f N . ,,N *t
cI N
0
N 0
tI N
:I - N
0 cl N)
/N N
X11
fl N
N
~_ -
N
N N N N
{)
74
CA 02726300 2010-12-22
o CI CI
N IN
O OMe O OMe
N N N
O O
N
04 N-\--,--N _~N N
-{~ N N/
N
O O
O H O
C N C N)
N~'N N, N N~ VNr
N-
O H O
H H O N H H O NN Cc,
N~/ H Fi O H H O
O O
NV-CNS CNSJ
qo H 0 H H O
N-S = N,S
N-\-/~r-N --/ N rN
N\_j
H O I H Fi O
102191 Another especially preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is selected from one of the radicals below:
CA 02726300 2010-12-22
0 0 0
O
N-~
N N I N-i
C
0 0 0 0
0
H 0 O O
N- N- N- N- N_I
O 0
0 0 0
H O H 0 H H 0 H H O
N-~ N-~ N-I
H 0 Fi 0 0 0
O H O 0 O
N- N- N-, N-1
O H O 0 0
And B is of the formula (f) below;
O R11
(R10) 1
P a,_ O N ,
(f)
Each R10 is independently selected from Hydrogen, halogen, C1-C4 alkyl,
hydroxyl,
azido, CN, NO2, OR6, NR6R7 , C02R6, CO NR6R7 where R6 and R7 are as described
above
and p is 0 or an integer from 1-4
R11 is selected from Hydrogen, or C1-C3 alkyl;
n is 0 or I
X is selected from CH2;
mis0orl
R1 and R2 are hydrogen;
102201 Another even more especially preferred embodiment of the invention
provides
compounds having the following structures. or a salt, hydrate, solvate, N-
oxide, or a
derivative thereof which is a prodrug wherein:
76
CA 02726300 2010-12-22
H H O H H O
I I N_~N O \ I N-'\,N O
O O Fi H- O
O O H O
NH~ 1 / N--\--N
O O O
H O O
H O
I I N'~N~ N'~N~ / \
O O H O O
O O
N
N~~~
O
O
[02211 Another more preferred embodiment of the invention provides compounds
having
structural Formula (I) shown above or a salt, hydrate, solvate or N-oxide
thereof or a
derivative thereof which is a prodrug wherein:
A is aryl or substituted aryl ;
B is of the formula (b) above
And R8 is either aryl, substituted aryl, or of the formula (c), or (d) below;
J (R9)o
N
(c)
J (R9)0
N
(d)
Where W and Y are independently selected from either N or CH and
Each R9 is independently selected from Hydrogen, halogen, C1-C3 alkyl, or
triflouromethyl and o is 0 or an integer from 1-3;
nis0or1
X is CH2.
mis 1 or2
77
CA 02726300 2010-12-22
R' and R2 are independently selected from hydrogen, halogen, hydroxy, cyano,
carboxy,C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 heteroalkyl, substituted
C1-C6
heteroalkyl, heteroaryl, substituted heteroaryl, OR3, or NR3R4;
R3-R4 are independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,
heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,
substituted
heteroarylalkyl, Acylamido , substituted acylamido, diacylamido, substituted
diacylamido or
alternatively, R3 and R4, together with the atoms to which they are bonded
form a
cycloheteroalkyl or substituted cycloheteroalkyl ring;
102221 Another even more preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is aryl or substituted aryl ;
B is of the formula (b) above
And R8 is of the formula (c), or (d) above;
Where W and Y are independently selected from either N or CH and
Each R9 is independently selected from Hydrogen, halogen, C1-C3 alkyl, or
triflouromethyl and o is 0 or an integer from 1-3;
nis0or1
X is CH2.
m is 1 or 2
R' and R2 are independently selected from hydrogen, halogen, hydroxy, cyano,
carboxy,Ci-C6 alkyl, substituted C1-C6 alkyl, C1-C6 heteroalkyl, substituted
C1-C6
heteroalkyl, heteroaryl, substituted heteroaryl, OR3, or NR3R4;
R3-R4 are independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,
heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,
substituted
heteroarylalkyl, Acylamido , substituted acylamido, diacylamido, substituted
diacylamido or
alternatively, R3 and R4, together with the atoms to which they are bonded
form a
cycloheteroalkyl or substituted cycloheteroalkyl ring;
78
CA 02726300 2010-12-22
[0223] Another even more preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is aryl or substituted aryl ;
B is of the formula (b) above
And R8 is of the formula (c), or (d) above;
Where W and Y are independently selected from either N or CH and
Each R9 is independently selected from Hydrogen, halogen, C1-C3 alkyl, or
triflouromethyl and o is 0 or an integer from 1-3;
nis0or1
X is CHZ.
m is 1 or 2
RI is hydrogen and R2 is selected selected from hydroxy, or OR3
R3-R4 are independently selected from the group consisting of hydrogen, C1-C3
alkyl,
substituted C1-C3 alkyl, acyl or substituted acyl
[0224] Another especially preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is aryl or substituted aryl ;
B is of the formula (b) above
And R8 is of the formula (d) above;
Each R9 is independently selected from Hydrogen, halogen, C1-C3 alkyl, or
triflouromethyl and o is 0 or an integer from 1-3;
n is 0 or 1
X is CHZ.
m is 1 or 2
R1 is hydrogen and R2 is selected selected from hydroxy, or OR3
R3-R4 are independently selected from the group consisting of hydrogen, C1-C3
alkyl,
substituted C1-C3 alkyl, acyl or substituted acyl
[0225] Another even more especially preferred embodiment of the invention
provides
compounds having the following structures. or a salt, hydrate, solvate, N-
oxide, or a
derivative thereof which is a prodrug wherein:
79
CA 02726300 2010-12-22
OH OH
F
N:/>-F N-
N\~N- ~\ NN-\ -F
N / \ OH N
F / ~ OH
N - ~~ N-
N / NN~N
OH
F
N\-~N \ F NT N -X F
OH N OH N
F
NN ON NN \ /
OH O` OH O
N N \N/ N N N /
F
N)-OH N-
N~~N-{\ NNN- ~\ OH
OH N OH N
N- - /~ N-
N\-~N-/N / N~ I /
CI OH Br OH
N:/>- - N-
N\- JN--~\ Nv " ~\ -F
N N
[02261 Another more preferred embodiment of the invention provides compounds
having
structural Formula (I) shown above or a salt, hydrate, solvate or N-oxide
thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (j) below;
R20
R9
N-
R18 r- -N
G)
Where R18 , R19 and R20 are independently selected from hydrogen, halogen,
hydroxy,
cyano, carboxy,C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 heteroalkyl,
substituted C1-C6
CA 02726300 2010-12-22
heteroalkyl, Aryl, substituted aryl, heteroaryl, substituted heteroaryl, OR3,
or NR3R4 or
alternatively, R18 and R19, or R19 and R20 together with the atoms to which
they are bonded
form a cycloalkyl or substituted cycloalkyl ring;
B is of the formula (b) above;
And R8 is of the formula (d) below;
N
(R9)0
N
(d)
Each R9 is independently selected from Hydrogen, halogen, C1-C3 alkyl, or
triflouromethyl and o is 0 or an integer from 1-3;
nis0or1
X is CH2.
mis1or2
R1 and R2 are independently selected from hydrogen, halogen, hydroxy, cyano,
carboxy,C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 heteroalkyl, substituted
C1-C6
heteroalkyl, heteroaryl, substituted heteroaryl, OR3, or NR3R4;
R3-R4 are independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,
heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,
substituted
heteroarylalkyl, Acylamido , substituted acylamido, diacylamido, substituted
diacylamido or
alternatively, R3 and R4, together with the atoms to which they are bonded
form a
cycloheteroalkyl or substituted cycloheteroalkyl ring;
102271 Another even more preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (j) below;
R20
R9e
N-
R18
(1)
Where R1s , R19 and R20 are independently selected from hydrogen, halogen,
hydroxy,
cyano, carboxy,C 1 -C6 alkyl, substituted C1-C6 alkyl, C1-C6 heteroalkyl,
substituted C1-C6
heteroalkyl, Aryl, substituted aryl, heteroaryl, substituted heteroaryl, OR3,
or NR3R4 or
81
CA 02726300 2010-12-22
alternatively, R' 8 and R'9, or R' 9 and R20 together with the atoms to which
they are bonded
form a cycloalkyl or substituted cycloalkyl ring;
B is of the formula (b) above;
And R8 is of the formula (d) below;
N
(R9)0
N
(d)
Each R9 is independently selected from Hydrogen, halogen, C1-C3 alkyl, or
triflouromethyl and o is 1;
n is I
X is CH2.
m is 1
R' and R2 are independently selected from hydrogen, halogen, hydroxy, cyano,
carboxy,C I -C6 alkyl, substituted C1-C6 alkyl, C1-C6 heteroalkyl, substituted
Ci-C6
heteroalkyl, heteroaryl, substituted heteroaryl, OR3, or NR3R4;
R3-R4 are independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,
heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,
substituted
heteroarylalkyl, Acylamido , substituted acylamido, diacylamido, substituted
diacylamido or
alternatively, R3 and R4, together with the atoms to which they are bonded
form a
cycloheteroalkyl or substituted cycloheteroalkyl ring;
[02281 Another especially preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (j) below;
R20
R9
N-
R1s ~N
G)
Where R'8 , R19 and R20 are independently selected from hydrogen, halogen,
hydroxy,
cyano, carboxy,C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 heteroalkyl,
substituted C1-C6
heteroalkyl, Aryl, substituted aryl, heteroaryl, substituted heteroaryl, OR3,
or NR3R4 or
82
CA 02726300 2010-12-22
alternatively, R'8 and R19, or R'9 and R20 together with the atoms to which
they are bonded
form a cycloalkyl or substituted cycloalkyl ring;
B is of the formula (b) above;
And R8 is of the formula (d) below;
N
J (R9)0
N
(d)
Each R9 is independently selected from Hydrogen, halogen, CI-C3 alkyl, or
triflouromethyl and o is 1;
n is 1
X is CH2.
m is l
R' and R2 are hydrogen
[02291 Another even more especially preferred embodiment of the invention
provides
compounds having the following structures. or a salt, hydrate, solvate, N-
oxide, or a
derivative thereof which is a prodrug wherein:
83
CA 02726300 2010-12-22
CI\ -N N~N~ ~N~- N--~ `>
N Br IN N N~N-~
N N ~ N
F N zN NN - / \ND O2NrN NN- N
N N N
CI
i
N \ I _
N N~N /N 3 N-\__/-N N `N)
Br O N
N
N N~N N~N) N N~ N-`/
N
N 0,0
O. S '
N ~/N
N~~ ~/N \ND N~- N \
H
H
\S N N ) S //
N
0 \Or- ~N \--DD 0 N N N~\-D
N N `-~ N
N
J
N N
0 N~--/N-\N) 0 \NN~- N- \)
N
\ I N N O N~ N /N--~N) /N--~N3
N,
N~ \--/N )
N
N
84
CA 02726300 2010-12-22
CI N N N N
N--~ N~ ~~N--K~F
N:~-F N N
N N
F N N N-/ 3 F r N N N--/\1 F
N N ~U N:\>-
H2N N N N- N F O2N N N NON F
N~- \--/ N_ N ~~ \---/ N::~
CI
N N
N-\--/- N- -/\/ N D~-F N~- U-/ ~F
N
Br 'O
\ I ~1 N \ I ,~ N
Nv-NN--/ :YF N \ =F
N N N
CI N ~N N
~Br
Q N~~-N N-~N
~~N~~ N:yBr N
OõO
F -- N N--{/ F
ci N N N N--~~N N
N
H H
N ~ N N N
O O N N---</ F OSO N N N-</ F
N N~N:
H H
IOI N N N- ~~N F IOI N IV N N-/ N F
N \--j N~ N~
N N/ NVN N- ( `~F
Or ~ N
O N ,i/N N N
CI N NNN CI N~~N~JN~N3-cl
N N
Nom.
N
N N NNE ~-F
N
[0230] Yet another more preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (k) below;
CA 02726300 2010-12-22
R21 XN,
O N O
R22
(k)
Where R21 and R22 are independently selected from hydrogen, C1-C6 alkyl,
substituted
C1-C6 alkyl, C1-C6 heteroalkyl, and substituted C1-C6 heteroalkyl,
B is of the formula (b) above;
And R8 is of the formula (d) below;
N
(R9)o
N
(d)
Each R9 is independently selected from Hydrogen, halogen, C1-C3 alkyl, or
triflouromethyl and o is 0 or an integer from 1-3;
n is 0 or 1
X is CH2.
m is 1 or 2
R1 and R2 are independently selected from hydrogen, halogen, hydroxy, cyano,
carboxy,C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 heteroalkyl, substituted
C1-C6
heteroalkyl, heteroaryl, substituted heteroaryl, OR3, or NR3R4;
R3-R4 are independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,
heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,
substituted
heteroarylalkyl, Acylamido , substituted acylamido, diacylamido, substituted
diacylamido or
alternatively, R3 and R4, together with the atoms to which they are bonded
form a
cycloheteroalkyl or substituted cycloheteroalkyl ring;
102311 Yet another even more preferred embodiment of the invention provides
compounds having structural Formula (I) shown above or a salt, hydrate,
solvate or N-oxide
thereof or a derivative thereof which is a prodrug wherein:
A is of the formula (k) below;
N,
R21 X
O N O
R22
86
CA 02726300 2010-12-22
(k)
Where R2' and R22 are independently selected from hydrogen, C1-C6 alkyl,
substituted
CI-C6 alkyl, C1-C6 heteroalkyl, and substituted C1-C6 heteroalkyl,
B is of the formula (b) above;
And R8 is of the formula (d) below;
N
(R9)o
N
(d)
Each R9 is independently selected from Hydrogen, halogen, C1-C3 alkyl, or
triflouromethyl and o is 1;
n is 0 or 1
X is CH2.
m is 1 or 2
R' and R2 are independently selected from hydrogen, halogen, hydroxy, cyano,
carboxy,Ci-C6 alkyl, substituted C1-C6 alkyl, C1-C6 heteroalkyl, substituted
C1-C6
heteroalkyl, heteroaryl, substituted heteroaryl, OR3, or NR3R4;
R3-R4 are independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,
heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,
substituted
heteroarylalkyl, Acylamido , substituted acylamido, diacylamido, substituted
diacylamido or
alternatively, R3 and R4, together with the atoms to which they are bonded
form a
cycloheteroalkyl or substituted cycloheteroalkyl ring;
[02321 Yet another especially preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (k) below;
R21 XN,N-it
O N O
R22
(k)
Where R21 and R22 are independently selected from hydrogen, CI-C3 alkyl, and
substituted C I -C3 alkyl,
87
CA 02726300 2010-12-22
B is of the formula (b) above;
And R8 is of the formula (d) below;
N
(R9)0
N
(d)
Each R9 is independently selected from Hydrogen, halogen, CI-C3 alkyl, or
triflouromethyl and o is 1;
nis0or1
X is CH2.
mis 1 or2
R1 and R2 are hydrogen,
[02331 Another even more especially preferred embodiment of the invention
provides
compounds having the following structures. or a salt, hydrate, solvate, N-
oxide, or a
derivative thereof which is a prodrug wherein:
N' N
( NN N N
N,NN N.Ni~/\iN I
ON~O O~N)--O N F
~N~N
O N 0 ' YN N`N NJ
NJ 0 N 0
I
[02341 Yet another more preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (1) below;
0
R22
~N N O
H R21
(1)
Where R21 and R22 are independently selected from hydrogen, CI-C6 alkyl,
substituted
CI-C6 alkyl, C1-C6 heteroalkyl, and substituted CI-C6 heteroalkyl,
B is of the formula (b) above;
And R8 is of the formula (d) below;
88
CA 02726300 2010-12-22
N
(R9)o
(d)
Each R9 is independently selected from Hydrogen, halogen, C1-C3 alkyl, or
triflouromethyl and o is 0 or an integer from 1-3;
nis0or1
X is CH2.
mis1or2
R' and R2 are independently selected from hydrogen, halogen, hydroxy, cyano,
carboxy,C I -C6 alkyl, substituted C1-C6 alkyl, C1-C6 heteroalkyl, substituted
C1-C6
heteroalkyl, heteroaryl, substituted heteroaryl, OR3, or NR3R4;
R3-R4 are independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,
heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,
substituted
heteroarylalkyl, Acylamido , substituted acylamido, diacylamido, substituted
diacylamido or
alternatively, R3 and R4, together with the atoms to which they are bonded
form a
cycloheteroalkyl or substituted cycloheteroalkyl ring;
102351 Yet another even more preferred embodiment of the invention provides
compounds having structural Formula (I) shown above or a salt, hydrate,
solvate or N-oxide
thereof or a derivative thereof which is a prodrug wherein:
A is of the formula (1) below;
0
R22
N N O
H R21
(1)
Where R21 and R22 are independently selected from hydrogen, CI-C6 alkyl,
substituted
CI-C6 alkyl, C1-C6 heteroalkyl, and substituted C1-C6 heteroalkyl,
B is of the formula (b) above;
And R8 is of the formula (d) below;
(R9 )o
N N
89
CA 02726300 2010-12-22
(d)
Each R9 is independently selected from Hydrogen, halogen, C1-C3 alkyl, or
triflouromethyl and o is 1;
nis0or1
XisCH2.
mis1or2
R1 and R2 are independently selected from hydrogen, halogen, hydroxy, cyano,
carboxy,C I -C6 alkyl, substituted C1-C6 alkyl, Ci-C6 heteroalkyl, substituted
C1-C6
heteroalkyl, heteroaryl, substituted heteroaryl, OR3, or NR3R4;
R3-R4 are independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,
heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,
substituted
heteroarylalkyl, Acylamido , substituted acylamido, diacylamido, substituted
diacylamido or
alternatively, R3 and R4, together with the atoms to which they are bonded
form a
cycloheteroalkyl or substituted cycloheteroalkyl ring;
[02361 Yet another especially preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (1) below;
0
R22
N X N O
N O
H R21
(1)
Where R21 and R22 are independently selected from hydrogen, C1-C3 alkyl, and
substituted C1-C3 alkyl,
B is of the formula (b) above;
And R8 is of the formula (d) below;
N
(Rs )0
(d)
Each R9 is independently selected from Hydrogen, halogen, C1-C3 alkyl, or
triflouromethyl and o is 1;
CA 02726300 2010-12-22
nis0orl
X is CH2.
mis 1 or 2
R' and R2 are hydrogen,
[0237] Another even more especially preferred embodiment of the invention
provides
compounds having the following structures. or a salt, hydrate, solvate, N-
oxide, or a
derivative thereof which is a prodrug wherein:
I (N N N (N N
OIN N'~'~~ O N N
I H H
F
~N N~ N N~ N N
0 H NJ O N N
H
O ~ N
LN N'N IN N
0, N N N J OINIH N
H J
N N N
NJ
O,
N N'
[0238] Yet another more preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (1) below;
O
22
I IOR-N NH R21
(1)
91
CA 02726300 2010-12-22
Where R21 and R22 are independently selected from hydrogen, C1-C6 alkyl,
substituted
C1-C6 alkyl, C1-C6 heteroalkyl, and substituted C1-C6 heteroalkyl,
B is of the formula (b) above and R8 is either aryl, substituted aryl,
nis0or1
Xis CH2.
mis 1 or2
R' and R2 are independently selected from hydrogen, halogen, hydroxy, cyano,
carboxy,Ci-C6 alkyl, substituted C1-C6 alkyl, C1-C6 heteroalkyl, substituted
C1-C6
heteroalkyl, heteroaryl, substituted heteroaryl, OR3, or NR3R4;
R3-R4 are independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,
heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,
substituted
heteroarylalkyl, Acylamido , substituted acylamido, diacylamido, substituted
diacylamido or
alternatively, R3 and R4, together with the atoms to which they are bonded
form a
cycloheteroalkyl or substituted cycloheteroalkyl ring;
[02391 Yet another even more preferred embodiment of the invention provides
compounds having structural Formula (I) shown above or a salt, hydrate,
solvate or N-oxide
thereof or a derivative thereof which is a prodrug wherein:
A is of the formula (1) below;
0
R22
~-N N O
H R21
(1)
Where R21 and R22 are independently selected from hydrogen, C1-C6 alkyl,
substituted
C1-C6 alkyl, C1-C6 heteroalkyl, and substituted C1-C6 heteroalkyl,
B is of the formula (b) above and R8 is either aryl, substituted aryl,
n is 0 or I
X is CH2.
mis1or2
R' and R2 are independently selected from hydrogen, C1-C6 alkyl, substituted
C1-C6
alkyl, CI-C6 heteroalkyl, substituted C1-C6 heteroalkyl,
92
CA 02726300 2010-12-22
[0240] Yet another especially preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (1) below;
0
R22
~N I N O
H R21
(1)
Where R21 and R22 are independently selected from hydrogen, C1-C3 alkyl,
B is of the formula (b) above and R8 is either aryl, substituted aryl,
n is 0 or I
X is CH2.
mis 1 or2
R1 and R2 are hydrogen,
[0241] Another even more especially preferred embodiment of the invention
provides
compounds having the following structures. or a salt, hydrate, solvate, N-
oxide, or a
derivative thereof which is a prodrug wherein:
Cl 0
N N.
ON I N%~.,r ~õ~N~ 0
0N ` N N
( H H
0 O 0
N N N
O N H `/ 1 0N N
I H
tJ C1 0 Ja
6r N
N- 0--N N
E7 N
H
C) F O
iN N" '`j rN
O N I N O N N I H H
93
CA 02726300 2010-12-22
CFg
O O
,,,_N N N
/~-N
H
N O~ N N'~ =, ' ^= ' N
H
CI
O
(;'NIN
H
102421 Yet another more preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (m) below;
H
R21 N,N1 N`
O N O
R22
(m)
Where R21 and R22 are independently selected from hydrogen, C1-C6 alkyl,
substituted
C1-C6 alkyl, C1-C6 heteroalkyl, and substituted C1-C6 heteroalkyl,
B is of the formula (b) above;
And R8 is of the formula (d) below;
N
;T-(R9)0
N
(d)
Each R9 is independently selected from Hydrogen, halogen, C1-C3 alkyl, or
triflouromethyl and o is 0 or an integer from 1-3;
nis0or1
X is CH2.
mis I or2
94
CA 02726300 2010-12-22
R' and R2 are independently selected from hydrogen, halogen, hydroxy, cyano,
carboxy,Ci-C6 alkyl, substituted C1-C6 alkyl, C1-C6 heteroalkyl, substituted
C1-C6
heteroalkyl, heteroaryl, substituted heteroaryl, OR3, or NR3R4;
R3-R4 are independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,
heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,
substituted
heteroarylalkyl, Acylamido , substituted acylamido, diacylamido, substituted
diacylamido or
alternatively, R3 and R4, together with the atoms to which they are bonded
form a
cycloheteroalkyl or substituted cycloheteroalkyl ring;
[0243] Yet another even more preferred embodiment of the invention provides
compounds having structural Formula (1) shown above or a salt, hydrate,
solvate or N-oxide
thereof or a derivative thereof which is a prodrug wherein:
A is of the formula (m) below;
,~
R2:N.N\ N~N N
N' 101Y
O N O
R22
(m)
Where R21 and R22 are independently selected from hydrogen, C1-C6 alkyl,
substituted
C1-C6 alkyl, C1-C6 heteroalkyl, and substituted C1-C6 heteroalkyl,
B is of the formula (b) above;
And R8 is of the formula (d) below;
N 9)0
N
(d)
Each R9 is independently selected from Hydrogen, halogen, C1-C3 alkyl, or
triflouromethyl and o is 1;
n is 0 or I
XisCH2.
mis1or2
R' and R2 are independently selected from hydrogen, halogen, hydroxy, cyano,
carboxy,C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 heteroalkyl, substituted
C1-C6
heteroalkyl, heteroaryl, substituted heteroaryl, OR3, or NR3R4;
CA 02726300 2010-12-22
R3-R4 are independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,
heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,
substituted
heteroarylalkyl, Ayylamido , substituted acylamido, diacylamido, substituted
diacylamido or
alternatively, R3 and R4, together with the atoms to which they are bonded
form a
cycloheteroalkyl or substituted cycloheteroalkyl ring;
102441 Yet another especially preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (m) below;
R2:N,N: NH
`
O N O
R22
(m)
Where R2' and R22 are independently selected from hydrogen, C1-C3 alkyl, and
substituted C1-C3 alkyl,
B is of the formula (b) above;
And R8 is of the formula (d) below;
N 9)0
~zz N
(d)
Each R9 is independently selected from Hydrogen, halogen, C1-C3 alkyl, or
triflouromethyl and o is 1;
nis0orl
XisCH2.
mis1or2
R1 and R2 are hydrogen,
[02451 Another even more especially preferred embodiment of the invention
provides
compounds having the following structures. or a salt, hydrate, solvate, N-
oxide, or a
derivative thereof which is a prodrug wherein:
96
CA 02726300 2010-12-22
N' N
0'y. O N O
N N y N N
"IN. ~~NJ
N H N N
N
I
O N O NN
0 N O
y (N' N y
H N, N N N N
H H
H N O
O~ N O O N,
N N 'N CN 1:r HN` N N /N`N H NJ
H
102461 Yet another more preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (m) below;
R 21 H
N,N N
O N 10
R22
(m)
Where R21 and R22 are independently selected from hydrogen, C1-C6 alkyl,
substituted
C1-C6 alkyl, C1-C6 heteroalkyl, and substituted C1-C6 heteroalkyl,
B is of the formula (b) above and R8 is either aryl, substituted aryl,
nis0or1
X is CH2.
mis1or2
R1 and R2 are independently selected from hydrogen, halogen, hydroxy, cyano,
carboxy,C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 heteroalkyl, substituted
CI-C6
heteroalkyl, heteroaryl, substituted heteroaryl, OR3, or NR3R4;
R3-R4 are independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,
heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,
substituted
heteroarylalkyl, Acylamido , substituted acylamido, diacylamido, substituted
diacylamido or
97
CA 02726300 2010-12-22
alternatively, R3 and R4, together with the atoms to which they are bonded
form a
cycloheteroalkyl or substituted cycloheteroalkyl ring;
102471 Yet another even more preferred embodiment of the invention provides
compounds having structural Formula (I) shown above or a salt, hydrate,
solvate or N-oxide
thereof or a derivative thereof which is a prodrug wherein:
A is of the formula (m) below;
H
R21
N -~,,
-N1 N
O N O
R22
(m)
Where R21 and R22 are independently selected from hydrogen, C1-C6 alkyl,
substituted
C1-C6 alkyl, C1-C6 heteroalkyl, and substituted C1-C6 heteroalkyl,
B is of the formula (b) above and R8 is either aryl, substituted aryl,
nis0or1
XisCH2.
m is 1 or 2
RI and R2 are independently selected from hydrogen, C1-C6 alkyl, substituted
C1-C6
alkyl, C1-C6 heteroalkyl, substituted C1-C6 heteroalkyl,
102481 Yet another especially preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (m) below;
H
R2:N.N1 N`P's
O N O
R22
(m)
Where R21 and R22 are independently selected from hydrogen, C1-C3 alkyl, B is
of the
formula (b) above and R8 is either aryl, substituted aryl,
nis0or1
XisCH2.
m is 1 or 2
98
CA 02726300 2010-12-22
R' and R2 are hydrogen,
[02491 Another even more especially preferred embodiment of the invention
provides
compounds having the following structures. or a salt, hydrate, solvate, N-
oxide, or a
derivative thereof which is a prodrug wherein:
O N 0 ( I O IV N O
y ~ N
N NN ",~ N,N N`~,e N H CF3 H CI
O N O O N O
Nom.-N N.N N
H H
I CF3
{
O N O N O N
H
H
CF3 CF3
b--,- H ON O O~ N O N N
HIV N HN.NN, ~..,..,~ N /
N H H
[02501 Yet another more preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (m) below;
R2: H
N.N\ N0- V
O N
R22
(m)
Where R21 and R22 are independently selected from hydrogen, CI-C6 alkyl,
substituted
C1-C6 alkyl, C1-C6 heteroalkyl, and substituted C1-C6 heteroalkyl,
B is of the formula (f) below;
99
CA 02726300 2010-12-22
O R11
(R10)
-11 P a,,, O Ny
Each R10 is independently selected from Hydrogen, halogen, C1-C4 alkyl,
hydroxyl,
azido, CN, NO2, OR6, NR6R7 , CO2R6, CO NR6R7 where R6 and R7 are as described
above
and p is 0 or an integer from 1-4
R11 is selected from Hydrogen, or C1-C3 alkyl;
nis0or1
X is CH2.
m is I or 2
R1 and R2 are independently selected from hydrogen, halogen, hydroxy, cyano,
carboxy,C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 heteroalkyl, substituted
C1-C6
heteroalkyl, heteroaryl, substituted heteroaryl, OR3, or NR3R4;
R3-R4 are independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,
heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,
substituted
heteroarylalkyl, Acylamido , substituted acylamido, diacylamido, substituted
diacylamido or
alternatively, R3 and R4, together with the atoms to which they are bonded
form a
cycloheteroalkyl or substituted cycloheteroalkyl ring;
[02511 Yet another even more preferred embodiment of the invention provides
compounds having structural Formula (I) shown above or a salt, hydrate,
solvate or N-oxide
thereof or a derivative thereof which is a prodrug wherein:
A is of the formula (m) below;
R2: H
N.Nl N~ .,
O N O
R22
(m)
Where R21 and R22 are independently selected from hydrogen, C1-C6 alkyl,
substituted
C 1-C6 alkyl, C 1-C6 heteroalkyl, and substituted C 1-C6 heteroalkyl,
B is of the formula (f) below;
100
CA 02726300 2010-12-22
R11
(R10) i I
P 00)"-" N ,
Each R10 is independently selected from Hydrogen, halogen, CI-C4 alkyl,
hydroxyl,
azido, CN, NO2, OR6, NR6R7 , C02R6, CO NR6R7 where R6 and R7 are as described
above
and p is 0 or an integer from 1-4
R11 is selected from Hydrogen, or C1-C3 alkyl;
nis0or1
XisCH2.
m is 1 or 2
R1 and R2 are independently selected from hydrogen, C1-C6 alkyl, substituted
CI-C6
alkyl, C1-C6 heteroalkyl, substituted C1-C6 heteroalkyl,
[02521 Yet another especially preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (m) below;
H
R21 N.N\ N`r'~
O N O
R22
(m)
Where R21 and R22 are independently selected from hydrogen, CI-C3 alkyl, B is
of the
formula (f) below;
R11
(R10) I
P 00)",-, Ny
Each R10 is independently selected from Hydrogen, halogen, C1-C4 alkyl,
hydroxyl,
azido, CN, NO2, OR6, NR6R7 , C02R6, CO NR6R7 where R6 and R7 are as described
above
and p is 0 or an integer from 1-4
R11 is selected from Hydrogen, or CI-C3 alkyl;
nis0orl
XisCH2.
101
CA 02726300 2010-12-22
m is 1 or 2
R1 and R2 are hydrogen,
[02531 Another even more especially preferred embodiment of the invention
provides
compounds having the following structures. or a salt, hydrate, solvate, N-
oxide, or a
derivative thereof which is a prodrug wherein:
0 N O O N 0 0
N N-N xJc
H H
102541 Another more preferred embodiment of the invention provides compounds
having
structural Formula (I) shown above or a salt, hydrate, solvate or N-oxide
thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (n) below;
0
(R12)p R23
0
(n)
Where each R12 is independently selected from Hydrogen, halogen, CI-C4 alkyl,
hydroxyl, azido, CN, NO2,, OR6, NR6R7 , C02R6, CO NR6R7 where R6 and R7 are as
described
above and p is 0 or an integer from 1-4
R23 is selected from hydrogen or halogen
B is of the formula (b) above
And R 8 is either aryl, substituted aryl, or of the formula (c), below;
J (R9)o
N
(c)
Where W and Y are independently selected from either N or CH and
Each R9 is independently selected from Hydrogen, halogen, C1-C3 alkyl, or
triflouromethyl and o is 0 or an integer from 1-2;
nis0or1
X is CH2.
mis1or2
102
CA 02726300 2010-12-22
R' and R2 are independently selected from hydrogen, halogen, hydroxy, cyano,
carboxy,Ci-C6 alkyl, substituted C1-C6 alkyl, C1-C6 heteroalkyl, substituted
C1-C6
heteroalkyl, heteroaryl, substituted heteroaryl, OR3, or NR3R4;
R3-R4 are independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,
heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,
substituted
heteroarylalkyl, Acylamido , substituted acylamido, diacylamido, substituted
diacylamido or
alternatively, R3 and R4, together with the atoms to which they are bonded
form a
cycloheteroalkyl or substituted cycloheteroalkyl ring;
[02551 Another even more preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (n) below;
0
(R12)P R23
0
(n)
Where each R12 is independently selected from Hydrogen, halogen, CI-C4 alkyl,
and p
is an integer from 1-2
R23 is halogen
B is of the formula (b) above
And R8 is either aryl, substituted aryl, or of the formula (c), below;
11 (R9)0
N
(c)
Where W and Y are independently selected from either N or CH and
Each R9 is independently selected from Hydrogen, halogen, C1-C3 alkyl, or
triflouromethyl and o is 0 or an integer from 1-2;
nis0or1
X is CH2.
mis 1 or2
103
CA 02726300 2010-12-22
R' and R2 are independently selected from hydrogen, halogen, hydroxy, cyano,
carboxy,Ci-C6 alkyl, substituted C1-C6 alkyl, C1-C6 heteroalkyl, substituted
C1-C6
heteroalkyl, heteroaryl, substituted heteroaryl, OR3, or NR3R4;
R3-R4 are independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,
heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,
substituted
heteroarylalkyl, Acylamido , substituted acylamido, diacylamido, substituted
diacylamido or
alternatively, R3 and R4, together with the atoms to which they are bonded
form a
cycloheteroalkyl or substituted cycloheteroalkyl ring;
[02561 Another especially preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (n) below;
0 ~R12)
P R23
O
(n)
Where each R12 is independently selected from Hydrogen, halogen, C1-C4 alkyl,
and p
is an integer from 1-2
R23 is halogen
B is of the formula (b) above
And R8 is either aryl, substituted aryl, or of the formula (c), below;
(R9)0
N
(c)
Where W is selected from either N or CH and Y is CH
R9 is Hydrogen, halogen,
nis0or1
X is CH2.
mis1or2
RI and R2 are hydrogen,
104
CA 02726300 2010-12-22
[0257] Another even more especially preferred embodiment of the invention
provides
compounds having the following structures. or a salt, hydrate, solvate, N-
oxide, or a
derivative thereof which is a prodrug wherein:
NJ N - __NJ N
0 CI 0 A CI
[0258] Another more preferred embodiment of the invention provides compounds
having
structural Formula (I) shown above or a salt, hydrate, solvate or N-oxide
thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (n) below;
0
N
(R1 2)p R23
0
(n)
Where each R12 is independently selected from Hydrogen, halogen, C1-C4 alkyl,
hydroxyl, azido, CN, NO2, OR6, NR6R7 , CO2R6, CO NR6R7 where R6 and R7 are as
described above and p is 0 or an integer from 1-4
R23 is selected from hydrogen or halogen
B is of the formula (p) below;
R24
R25
R8
N
(p)
Where R24 and R25 are independently selected from hydrogen, hydroxyl, OR6
where
R6 is as described above or alternatively, R24 and R25 together with the atoms
to which they
are bonded form a carbon-carbon double bond.
And R8 is either aryl, substituted aryl, or of the formula (c), below;
;5 (R9)o
(c)
Where W and Y are independently selected from either N or CH and
105
CA 02726300 2010-12-22
Each R9 is independently selected from Hydrogen, halogen, C1-C3 alkyl, or
triflouromethyl and o is 0 or an integer from 1-2;
nis0or1
Xis CH2.
mis 1 or2
R' and R2 are independently selected from hydrogen, halogen, hydroxy, cyano,
carboxy,Ci-C6 alkyl, substituted C1-C6 alkyl, C1-C6 heteroalkyl, substituted
C1-C6
heteroalkyl, heteroaryl, substituted heteroaryl, OR3, or NR3R4;
R3-R4 are independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,
heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,
substituted
heteroarylalkyl, Acylamido , substituted acylamido, diacylamido, substituted
diacylamido or
alternatively, R3 and R4, together with the atoms to which they are bonded
form a
cycloheteroalkyl or substituted cycloheteroalkyl ring;
[02591 Another even more preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (n) below;
0 (R12)p C11- ,O
(n)
Where each R12 is independently selected from Hydrogen, halogen, C1-C4 alkyl,
and p
is an integer from 1 -2
R23 is selected from hydrogen or halogen
B is of the formula (p) below;
R24
RR8
N
(p)
106
CA 02726300 2010-12-22
Where R24 and R25 are independently selected from hydrogen, hydroxyl, OR6
where
R6 is as described above or alternatively, R24 and R25 together with the atoms
to which they
are bonded form a carbon-carbon double bond.
And R8 is either aryl, substituted aryl, or of the formula (c), below;
(R9)o
N
(c)
Where W and Y are independently selected from either N or CH and
Each R9 is independently selected from Hydrogen, halogen, C1-C3 alkyl, or
triflouromethyl and o is 0 or an integer from 1-2;
nis0orl
X is CH2.
mis I or2
R' and R2 are hydrogen,
102601 Another especially preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (n) below;
0
:R1zlp O_Rz3
C"_1
(n)
Where each R12 is independently selected from Hydrogen, halogen, C1-C4 alkyl,
and p
is an integer from 1-2
R23 is selected from hydrogen or halogen
B is of the formula (p) below;
R24
Res
R8
N
(p)
107
CA 02726300 2010-12-22
Where R24 and R25 are independently selected from hydrogen, hydroxyl, OR6
where
R6 is as described above or alternatively, R24 and R25 together with the atoms
to which they
are bonded form a carbon-carbon double bond.
And R8 is either aryl, substituted aryl, or of the formula (c), below;
W^Y
~~ J (R9)o
N
(c)
Where W is either N or CH and Y is CH
Each R9 is Hydrogen, or halogen, and o is an integer from 1-2;
nis0orl
Xis CH2.
m is 1 or 2
RI and R2 are hydrogen,
102611 Another even more especially preferred embodiment of the invention
provides
compounds having the following structures. or a salt, hydrate, solvate, N-
oxide, or a
derivative thereof which is a prodrug wherein:
N N
N~~N N ~N ~N N
C~~ C~~ \ 0
O'er CI O_'' `CI
O CI
c~fNNNcYQ
102621 Another even more preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (q) below;
H
O N OY
(q)
Where the dashed line represents either a single or a double bond
is of the formula (b) above and R8 is either aryl, or substituted aryl,
108
CA 02726300 2010-12-22
nis0or1
X is CH2.
m is 1 or2
R1 and R2 are independently selected from hydrogen, C1-C6 alkyl, substituted
C1-C6
alkyl, C1-C6 heteroalkyl, substituted C1-C6 heteroalkyl,
[0263] Another especially preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (q) below;
H
O ~"NOY
(q)
Where the dashed line represents either a single or a double bond
B is of the formula (b) above and R8 is either aryl, or substituted aryl,
nis0orl
XisCH2.
mis 1 or2
R1 and R2 are hydrogen,
[0264] Another even more especially preferred embodiment of the invention
provides
compounds having the following structures. or a salt, hydrate, solvate, N-
oxide, or a
derivative thereof which is a prodrug wherein:
H H
O N 0~=~~N~ i0 OWN N"') '0
N N
109
CA 02726300 2010-12-22
O N N 0 O N O ~~N O
H H
O T"~V 0'/'=N") Cl O N CI
~N I CI ~N I CI
O N O N IN
~N CI ~,N CI
H H
O N O---~~ N CI 0 N 0""-~N'-') CI
102651 Another more preferred embodiment of the invention provides compounds
having
structural Formula (I) shown above or a salt, hydrate, solvate or N-oxide
thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (r) below;
(R12)p
N
R26
(r)
Where each RI2 is independently selected from Hydrogen, halogen, CI-C4 alkyl,
hydroxyl, azido, CN, NO2, OR6, NR6R7 , C02R6, CO NR6R7 where R6 and R7 are as
described above and p is 0 or an integer from 1-4
R26 is selected from hydrogen or CI-C4 alkyl,
B is of the formula (b) above
And R8 is either aryl, substituted aryl,
nis0orl
X is CH2.
mis1or2
110
CA 02726300 2010-12-22
R' and R2 are independently selected from hydrogen, halogen, hydroxy, cyano,
carboxy,Ci-C6 alkyl, substituted C1-C6 alkyl, C1-C6 heteroalkyl, substituted
C1-C6
heteroalkyl, heteroaryl, substituted heteroaryl, OR3, or NR3R4;
R3-R4 are independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,
heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,
substituted
heteroarylalkyl, Acylamido , substituted acylamido, diacylamido, substituted
diacylamido or
alternatively, R3 and R4, together with the atoms to which they are bonded
form a
cycloheteroalkyl or substituted cycloheteroalkyl ring;
[0266] Another even more preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (r) below;
(R 12)p C"!5,~6N
R26
(r)
Where each R12 is independently selected from Hydrogen, halogen, C1-C4 alkyl,
hydroxyl, azido, CN, NO2, OR6, NR6R7 , CO2R6, CO NR6R7 where R6 and R7 are as
described above and p is 0 or an integer from 1-4
R26 is selected from hydrogen or C1-C4 alkyl,
B is of the formula (b) above
And R8 is either aryl, substituted aryl,
nis0orl
X is CH2.
in is 1 or 2
R' and R2 are hydrogen,
[0267] Another especially preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (r) below;
111
CA 02726300 2010-12-22
~R12)p
R26
(r)
Where each R12 is independently selected from Hydrogen, halogen, C,-C4 alkyl,
hydroxyl, azido, CN, NO2, OR6, NR6R7 , CO2R6, CO NR6R7 where R6 and R7 are as
described above and p is 0 or an integer from 1-4
R26 is selected from hydrogen or C1-C4 alkyl,
B is of the formula (b) above
And R8 is either a benzofuran-5-yl, 2,3-dihydrobenzofuran-5-yl, chroman-6-yl,
chroman-4-on-6-yl which is unsubstituted or monosubstituted by CN, OH, CH2OH,
CH2OR3, CO R3
nis0or1
X is CH2.
m is I or 2
R' and R2 are hydrogen,
[02681 Another even more especially preferred embodiment of the invention
provides
compounds having the following structures. or a salt, hydrate, solvate, N-
oxide, or a
derivative thereof which is a prodrug wherein:
0 Nth
N-
N
N-H
H
112
CA 02726300 2010-12-22
NH2
HO--
HO-~
N-
IJ O QH MHz
N
rDN
N- 0
O HO--,,
R3--
N
< N Jj c/ f}} Y,~, v Nti~
rt N N--
N` H
H
30-
N N
N,
H'
N
N N`
H H }~ !
N/
H Ci
R3O- I I
N,~'~ N
IN
N J N
H
N
H
113
CA 02726300 2010-12-22
00 HO--- ~. '
H i. 1 N
Rat -- 0
N
0
N."
H
[02691 Another more preferred embodiment of the invention provides compounds
having
structural Formula (I) shown above or a salt, hydrate, solvate or N-oxide
thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (r) below;
(R12)p
6NN
R26
(r)
Where each R12 is independently selected from Hydrogen, halogen, C1-C4 alkyl,
hydroxyl, azido, CN, NO2, OR6, NR6R7 , C02R6, CO NR6R7 where R6 and R7 are as
described above and p is 0 or an integer from 1-4
R26 is selected from hydrogen or C1-C4 alkyl,
B is of the formula (p) below;
R24
1R8
N
(p)
Where R24 and R25 are independently selected from hydrogen, hydroxyl, OR6
where
R6 is as described above or alternatively, R24 and R25 together with the atoms
to which they
are bonded form a carbon-carbon double bond.
And R8 is either aryl, substituted aryl, or of the formula (c), below;
114
CA 02726300 2010-12-22
9
1 (R)0
VN
(c)
Where W and Y are independently selected from either N or CH and
Each R9 is independently selected from Hydrogen, halogen, CI-C3 alkyl, or
triflouromethyl and o is 0 or an integer from 1-2;
nis0or1
X is CH2.
m is I or 2
R' and R2 are independently selected from hydrogen, halogen, hydroxy, cyano,
carboxy,Ci-C6 alkyl, substituted C1-C6 alkyl, CI-C6 heteroalkyl, substituted
C1-C6
heteroalkyl, heteroaryl, substituted heteroaryl, OR3, or NR3R4;
R3-R4 are independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,
heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,
substituted
heteroarylalkyl, Acylamido , substituted acylamido, diacylamido, substituted
diacylamido or
alternatively, R3 and R4, together with the atoms to which they are bonded
form a
cycloheteroalkyl or substituted cycloheteroalkyl ring;
102701 Another even more preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (r) below;
(R12)p i 6N
R26
(r)
Where each R12 is independently selected from Hydrogen, halogen, CI-C4 alkyl,
hydroxyl, azido, CN, NO2, OR6, NR6R7 , CO2R6, CO NR6R' where R6 and R' are as
described above and p is 0 or an integer from 1-4
R26 is selected from hydrogen or C1-C4 alkyl,
B is of the formula (p) below;
115
CA 02726300 2010-12-22
R24
R25
R8
N
(p)
Where R24 and R25 are either both hydrogen, or alternatively, R24 and R25
together
with the atoms to which they are bonded form a carbon-carbon double bond.
And R8 is either aryl, substituted aryl, or of the formula (c), below;
(R9)0
Vj"-
(c)
Where W and Y are independently selected from either N or CH and
Each R9 is independently selected from Hydrogen, halogen, C1-C3 alkyl, or
triflouromethyl and o is 0 or an integer from 1-2;
nis0or1
XisCH2.
mis I or2
R' and R2 are hydrogen,
102711 Another especially preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (r) below;
\x
12)p
i /
N
R26
(r)
Where each R12 is independently selected from Hydrogen, halogen, C1-C4 alkyl,
hydroxyl, CN, NO2, OR6, NRbR7 , CO2R6, CO NR6R 7 where R6 and R7 are as
described
above and p is 1
R26 is selected from hydrogen or CI-C4 alkyl,
B is of the formula (p) below;
116
CA 02726300 2010-12-22
R24
RR8
N
(p)
Where R24 and R25 are either both hydrogen, or alternatively, R24 and R25
together
with the atoms to which they are bonded form a carbon-carbon double bond.
And R8 is aryl or substituted aryl,
nis0or1
X is CH2.
mis 1 or2
R' and R2 are hydrogen,
[02721 Another even more especially preferred embodiment of the invention
provides
compounds having the following structures. or a salt, hydrate, solvate, N-
oxide, or a
derivative thereof which is a prodrug wherein:
N N N N N
OH
HO HO
H HO ' N H H HO N H CI H
N N N N
HO HO CI
H HO H CI N HO N
[0273] Yet another more preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (r) below;
117
CA 02726300 2010-12-22
R28
N, R27
00
(r)
Where R28 is selected from hydrogen or C1-C6 alkyl, substituted C1-C6 alkyl,
C1-C6
heteroalkyl, and substituted C1-C6 heteroalkyl,
and R27 is selected from C1-C8 alkyl, substituted C1-C8 alkyl, C1-C8
heteroalkyl, and
substituted C1-C8 heteroalkyl, aryl, and substituted aryl
B is of the formula (b) above and R8 is either aryl, substituted aryl,
heteroaryl or
substituted heteroarly
nis0or1
X is CH2.
m is 1 or 2
R' and R2 are independently selected from hydrogen, halogen, hydroxy, cyano,
carboxy,C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 heteroalkyl, substituted
C1-C6
heteroalkyl, heteroaryl, substituted heteroaryl, OR3, or NR3R4;
R3-R4 are independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,
heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,
substituted
heteroarylalkyl, Acylamido , substituted acylamido, diacylamido, substituted
diacylamido or
alternatively, R3 and R4, together with the atoms to which they are bonded
form a
cycloheteroalkyl or substituted cycloheteroalkyl ring;
(02741 Yet another even more preferred embodiment of the invention provides
compounds having structural Formula (I) shown above or a salt, hydrate,
solvate or N-oxide
thereof or a derivative thereof which is a prodrug wherein:
A is of the formula (r) below;
R28
HIV, R27
00
(r)
Where R28 is selected from hydrogen or C1-C6 alkyl, substituted C1-C6 alkyl,
C1-C6
heteroalkyl, and substituted C1-C6 heteroalkyl,
118
CA 02726300 2010-12-22
and R27 is selected from C1-C8 alkyl, substituted CI-C8 alkyl, CI-C8
heteroalkyl, and
substituted C1-C8 heteroalkyl, aryl, and substituted aryl
B is of the formula (b) above and R8 is either aryl, substituted aryl,
heteroaryl or
substituted heteroarly
nis0or1
XisCH2.
m is 1 or 2 and
R' and R2 are hydrogen
102751 Yet another especially preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (r) below;
R28
N, R27
00
(r)
Where R28 is selected from hydrogen or methyl
and R27 is selected from C1-C8 alkyl, substituted C1-C8 alkyl, CI-C8
heteroalkyl, and
substituted C1-C8 heteroalkyl, aryl, and substituted aryl
B is of the formula (b) above and R8 is either aryl, substituted aryl,
heteroaryl or
substituted heteroarly
n is 0 or I
Xis CH2.
m is 1 or 2 and
R' and R2 are hydrogen
102761 Yet another even more especially preferred embodiment of the invention
provides
the following compounds or a salt, hydrate, solvate or N-oxide thereof or a
derivative thereof
which is a prodrug:
119
CA 02726300 2010-12-22
U-11
" H
r N ~~s Sti~\ o N
N H ( N
02N
N N O%
O
i
H N \ I H
0
N . \ N O O N~ N
Or
H p
H
N i
S~'~' N' \.~ \ N5
H ~t~ H Q NO
N,~ O O SN N
H
H
N^`/\ N,S N,
O
N O2N
N N O/S\
ao
N N S~
NN~~~ N O~
O
N
H H
O O N ~~'' N^S \ N'~ NS\
O
O ..
o =O
S N
O O
i
H I H
N \ II
N,
\I ` N~ NO S\ O \ I N I os0
;ter
SO N '-O N~~ Hr
N--'--" N ,S N ~\ / \e N
0 H O H
r O
F
p ( IN \ NK H
I 'N~\/`~~N
O H
~.
H
r'Nr~ S J NN S \ Ii
N \ N~ 110 H
N N J O 110
120
CA 02726300 2010-12-22
H
N N
H
N
O ~ SO
N
N
H
~
Ij
O (SIN ;` 0 r' N
S N^,/ ` N~1 O.'-N~ iN..s
H H
o N O IN N
~S.N.~y.N~ NN
H f I ~/J O H / I OI
O '~ = N ' N O N -'~/
J O H H
H
NJC:rN,,~ -YN N,_)
O O `/
H O
H I N '=~= 0
N ,/~ O S H
O C
O
O~ H N\
H
[0277] Yet another more preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (s) below;
O N
R12
(S)
Where R12 is selected from Hydrogen, halogen, C1-C4 alkyl, hydroxyl, azido,
CN,
NO2, OR3, NR3R4 , CO2R3, CO NR3R4 where R3 and R4 are as described above and
the
dashed line represents a single or a double bond;
B is of the formula (b) above and R8 is either aryl, substituted aryl,
heteroaryl or
substituted heteroarly
121
CA 02726300 2010-12-22
nis0orI
X is CH2.
mis 1 or2
R' and R2 are independently selected from hydrogen, halogen, hydroxy, cyano,
carboxy,Ci-C6 alkyl, substituted C1-C6 alkyl, C1-C6 heteroalkyl, substituted
C1-C6
heteroalkyl, heteroaryl, substituted heteroaryl, OR3, or NR3R4;
R3-R4 are independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,
heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,
substituted
heteroarylalkyl, Acylamido , substituted acylamido, diacylamido, substituted
diacylamido or
alternatively, R3 and R4, together with the atoms to which they are bonded
form a
cycloheteroalkyl or substituted cycloheteroalkyl ring;
[0278] Yet another even more preferred embodiment of the invention provides
compounds having structural Formula (I) shown above or a salt, hydrate,
solvate or N-oxide
thereof or a derivative thereof which is a prodrug wherein:
A is of the formula (s) below;
O N
R12
(s)
Where R12 is selected from Hydrogen, halogen, C1-C4 alkyl, hydroxyl, azido,
CN,
NO2, OR3, NR3R4 , CO2R3, CO NR3R4 where R3 and R4 are as described above and
the
dashed line represents a single or a double bond;
B is of the formula (b) above and R8 is either aryl, substituted aryl,
heteroaryl or
substituted heteroaryl
nis0or1
X is CH2.
mis I or2
R' and R2 are hydrogen
R3-R4 are independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,
heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,
substituted
122
CA 02726300 2010-12-22
heteroarylalkyl, Acylamido , substituted acylamido, diacylamido, substituted
diacylamido or
alternatively, R3 and R4, together with the atoms to which they are bonded
form a
cycloheteroalkyl or substituted cycloheteroalkyl ring;
(0279] Yet another especially preferred embodiment of the invention provides
compounds
having structural Formula (I) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
A is of the formula (s) below;
O N
R12
(S)
Where R12 is selected from Hydrogen, halogen, methoxy, or ethoxy
B is of the formula (b) above and R8 is either aryl, substituted aryl,
heteroaryl or
substituted heteroaryl
nis0
X is CH2.
mis t
R' and R2 are hydrogen
(0280] Yet another even more especially preferred embodiment of the invention
provides
the following compounds or a salt, hydrate, solvate or N-oxide thereof or a
derivative thereof
which is a prodrug:
123
CA 02726300 2010-12-22
CI Br NO2 CF3
~ \ N \ ~~ v N \ N J
O N O N O N \ O N
110
CI O~ O~ NO2
N \ N \ N N \ N
OT-- O TO N O_
-,,-,0 CI ,O CI
OH CI CI
N N N r'N
N N")
O N \ O N O T-~9 O N \
CI ,-O ,O
CF3 Br
/ CI CI /
rN N N
O N \ 0 O N \ 0 WN
[02811 In another aspect of the invention, compounds of structural Formula
(II) and (III)
are provided:
124
CA 02726300 2010-12-22
8 0 R27
R,N^ N,SO
N
(II)
R$ IN
P
0''-R27
(III)
or a salt, hydrate, solvate or N-oxide thereof or a derivative thereof which
is a prodrug
wherein:
Where R8 is selected from the group consisting of aryl, substituted aryl,
heteroaryl,
substituted heteroaryl, heteroalkyl and substituted heteroalkyl,
and R27 is selected from C1-C8 alkyl, substituted CI-C8 alkyl, C1-C8
heteroalkyl, and
substituted C1-C8 heteroalkyl, aryl, and substituted aryl
[02821 Another even more preferred embodiment on the invention provides,
compounds
of structural Formula (II) or (III) or a salt, hydrate, solvate or N-oxide
thereof or a derivative
thereof which is a prodrug wherein:
Where R8 is selected from the group consisting of aryl, substituted aryl,
heteroaryl,
substituted heteroaryl,
and R27 is selected from C1-C8 alkyl, substituted C1-C8 alkyl, C1-C8
heteroalkyl, and
substituted C1-C8 heteroalkyl, aryl, and substituted aryl
[02831 Another especially preferred embodiment on the invention provides,
compounds of
structural Formula (II) or (III) or a salt, hydrate, solvate or N-oxide
thereof or a derivative
thereof which is a prodrug wherein:
Where R8 is selected from the group consisting of aryl, substituted aryl,
heteroaryl,
substituted heteroaryl,
and R27 is selected from C1-C8 alkyl, aryl, and substituted aryl
[02841 Yet another even more especially preferred embodiment of the invention
provides
the following compounds or a salt, hydrate, solvate or N-oxide thereof or a
derivative thereof
which is a prodrug:
125
CA 02726300 2010-12-22
F
F
0
IN
N I/ N N
N- IN p I N
~IN\/~/
/
O I p\ \ N N N.O
AN N ~ N ~p /~
H O-C~\ -~o
Q-N / S
S HN
J N JN p O
HN
[02851 Another aspect, a compound of structural Formula (IV) is provided:
X' H\\' \\H
N
B
(IV)
or a salt, hydrate, solvate or N-oxide thereof or a derivative thereof which
is a prodrug
wherein:
A and B are independently selected from the group consisting of alkyl
substituted
alkyl, alkenyl, substituted alkenyl, alkynyl substituted alkynyl, alkoxy,
substituted alkoxy,
alkylthio, substituted alkylthio, alkylaryl, substituted alkylaryl,
alkoxyaryl, substituted
alkoxyaryl, aryl, substituted aryl, aryloxy, substituted aryloxy, heteroaryl,
substituted
heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroalkyl, substituted
heteroalkyl,
OR3, S(O)bR3, NR3R4, SO2NR3R4, NR3SO2R4, NR3SOZNR4R5;
b=0,1,or2
R3-R5 are independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,
heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,
substituted
heteroarylalkyl, Acylamido , substituted acylamido, diacylamido, substituted
diacylamido or
alternatively, R3 and R4, R3 and R5, or R4 and R5, together with the atoms to
which they are
bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
126
CA 02726300 2010-12-22
[02861 Another more preferred embodiment on the invention provides, compounds
of
structural Formula (IV) or a salt, hydrate, solvate or N-oxide thereof or a
derivative thereof
which is a prodrug wherein:
A H" ,H
N
~N,B
(IV)
A is selected from the following radicals;
0 0 0
0 N
N N N-~ N
N-~
z N
C
O O 0 0
o
H O O O
N._. C1 N_. N_1 N , N_1
O O
O o
H O H O H H 0 H H O
N---~ N`1 N-j .... C N-1
H O Fi O H H O H O
127
CA 02726300 2010-12-22
O H O O O
N-~ N---~ N-j N-1
(
C
O p O O
\--\'N-1L O O \,N-0-& O N %\
N_
U O N,
O O O N
O 0 O
F CI
N- I N- N-
.O N N
Ci I S 11
01 O h 0 O
O
Br Br
N-
0
and B is selected from the group consisting of aryl, substituted aryl,
aryloxy,
substituted aryloxy, heteroaryl, and substituted heteroaryl,
[02871 Another more preferred embodiment on the invention provides, compounds
of
structural Formula (IV) or a salt, hydrate, solvate or N-oxide thereof or a
derivative thereof
which is a prodrug wherein:
A is selected from the following radicals;
O O O
O
N N- N N N-1
r N
0 O O O
o 0
H 0 O O
-J~ C N-1 C N-1 N-, N-'
0 0
H O O O
128
CA 02726300 2010-12-22
H 0 H O H H 0 H H 0
N-1 N-1 da N-1 N
H O H O H H O H H O
0 H 0 0 0
C N- N- N- N
0 H 0 0 0
0 O ~y-NSL 0
0 N
N-_
O O N 0 0 O O
0 0 0
CI
I N- wc~N...NC! i
0 66 b O N N
0
Br~~N-1 Br ~- N N-~
~N N
0
and B is of the formula (c), below;
I ~ (R9)
`/ o
\N
(c)
Where W and Y are independently selected from either N or CH and
Each R9 is independently selected from Hydrogen, halogen, C1-C3 alkyl, or
triflouromethyl and o is 0 or an integer from 1-2;
102881 Another especially embodiment on the invention provides, compounds of
structural Formula (IV) or a salt, hydrate, solvate or N-oxide thereof or a
derivative thereof
which is a prodrug wherein:
A is selected from the following radicals;
129
CA 02726300 2010-12-22
0 0 0
2T N N- <N_ N- OLIN-
N
0 0 0 0
O 0
H 0 O O
N_, CN_ N-, N-~ N-~
C.. 0 0
0 O O
H 0 H 0 H H 0 H Z~-
N-~ N-1
N-i 0 11 -
- -4
H 0 CA 0 Fi H 0 H H 0
0 H 0 0 0
EC N-1 NA C4
0 H 0 0 0
~N 0 --'\\-N-& 0 \-N-& O NN-
N'N
O O N) 0 O N O O N
0 0 0
N- F / N- I / S N- N N- CI N-
CI N
00 00 O
0
Br Br \
N-~ N-1 , N-j
0
and B is of the formula (c), below;
1 (R9)0
\N
(c)
Where W is either N or CH, Y is CH and
Each R9 is independently selected from Hydrogen, halogen, CI-C3 alkyl, or
triflouromethyl and o is 0 or an integer from 1-2;
130
CA 02726300 2010-12-22
[0289] Another even more especially preferred embodiment of the invention
provides
compounds having the following structures. or a salt, hydrate, solvate, N-
oxide, or a
derivative thereof which is a prodrug wherein:
O O rNfl: NON` H' H
N H N H N N
N NN
O ~N N O ~N N
~~ II 1 N / N J
N
O O
N H H N H`' H N N H H ~N H' H
N~
O N N O N N N NN
~( I I N O IN
O O N O
N H' H N H H N H H N H .H
N
O O
O ~ O N N N
~ NN
N
N/ NJ N/ NJ
N
O O O O
N H' H N H H N H H N H' H
O N O LN N O N O N N
N N N N
CI CI _
/\N N H,.H
N H H N
N N
~N N~N~
ll'
NJ
N /
[0290] Another preferred embodiment of the invention provides compounds having
structural Formula (V) shown below or a salt, hydrate, solvate or N-oxide
thereof or a
derivative thereof which is a prodrug wherein:
R31
R29 X2 ~
R28' N R32
V
R28 and R29 are independently selected from the group consisting of hydrogen,
alkyl
substituted alkyl, alkenyl, substituted alkenyl, alkynyl substituted alkynyl,
alkoxy, substituted
alkoxy, alkylthio, substituted alkylthio, alkylaryl, substituted alkylaryl,
alkoxyaryl,
substituted alkoxyaryl, aryl, substituted aryl, aryloxy, substituted aryloxy,
heteroaryl,
131
CA 02726300 2010-12-22
substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroalkyl,
substituted
heteroalkyl,
X2 is selected from N or CH and R31 and R32 are independently selected from
Hydrogen or C1- C3 alkyl. In some examples, one R31 or R32 is hydrogen and the
other R31
or R32 together with X2 when X2 is C can form a carbon carbon double bond.
Another more preferred embodiment of the invention provides compounds having
structural Formula (V) shown above or a salt, hydrate, solvate or N-oxide
thereof or a
derivative thereof which is a prodrug wherein:
R28 and R29 are independently selected from the group consisting of alkyl
substituted
alkyl, aryl, substituted aryl, heteroaryl,
X2 is selected from N or CH and R31 and R32 are independently selected from
Hydrogen or C1- C3 alkyl. In some examples, one R31 or R32 is hydrogen and the
other R3'
or R32 together with X2 when X2 is C can form a carbon carbon double bond.
[0291] Another even more preferred embodiment of the invention provides
compounds
having structural Formula (V) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
R28 is a substituted aryl group and R29 is selected from the group consisting
of C1-
C6 alkyl, C3 - C7 cycloalkylmethyl, arylmethyl, or substituted arylmethyl.
X2 is N and R31 and R32 are independently selected from Hydrogen or methyl.
[0292] Another especially preferred embodiment of the invention provides
compounds
having structural Formula (V) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
R28 is selected from the following radicals:
132
CA 02726300 2010-12-22
H
0 I O q0 9::) O O H H
\ O CN \ \ \ -N >=0
/ O 0 S O
H
~QqQpQ90
and R29 is selected from the group consisting of C1 C6 alkyl, C3 - C7
cycloalkylmethyl, arylmethyl, or substituted arylmethyl.
X2 is N and R3' and R32 are independently selected from Hydrogen or methyl.
[02931 Another even more especially preferred embodiment of the invention
provides
compounds having structural Formula (V) shown above or a salt, hydrate,
solvate or N-oxide
thereof or a derivative thereof which is a prodrug wherein:
R28 is selected from the following radicals:
H
O I~ O I~ 0 S VO)
oO O H H
/ O/ 0 0 S O
13
90S 10) O Oi
and R29 is selected from the the following radicals:
133
CA 02726300 2010-12-22
F
F F
/ \
N N- - - - -
F oF
F CI Br
'CX~ ?NI
X2 is N and R31 and R32 are independently selected from Hydrogen or methyl.
10294] Another even more especially preferred embodiment of the invention
provides
compounds having the following structures. or a salt, hydrate, solvate, N-
oxide, or a
derivative thereof which is a prodrug wherein:
/ \ / \
\ / N \ / - N
N N 0 N \ /
N- N qiO NJ NJ
\ /
NH o~O Hio \ / 0 H\ / NH
o
H N / \
/ N N> J '20 No\ /
q NJ NH N_ N
- 0 \ / o -
0 \ / o
0
134
CA 02726300 2010-12-22
/
N NJ N~ N NN N
_ -
O NJ / O O / O
O O~ O
- o - N / N N /
N
N
N C60 NJ
cbo qo cb q135
CA 02726300 2010-12-22
F F
N- N-
N N 2/ N N/
N N
NJ
N NJ N 0-0 0- 0
0 H O OJ N111O
H
F F F
F
NN IN N IN
NN
NJ NJ ~~1 NJ
N
0-0 N~ 0-0 O
OJ H O J N-~-'O
O H
F F
NCN
C 0 0-0
O Hip
[02951 Another especially preferred embodiment of the invention provides
compounds
having structural Formula (V) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
R28 is selected from the following radicals:
136
CA 02726300 2010-12-22
0 0J (?~O) VO)
J
H
C) N > >=0
O/ I/ N S O
H
pc(2 I ~ Ni p 0 i qaN H
qaN
O 011-1
O 00
and R29 is selected from the group consisting of hydrogen, or Ci - C3 alkyl,
X2 is N and R3' and R32 are independently selected from Hydrogen or methyl.
[0296] Another even more especially preferred embodiment of the invention
provides
compounds having structural Formula (V) shown above or a salt, hydrate,
solvate or N-oxide
thereof or a derivative thereof which is a prodrug wherein:
R28 is selected from the following radicals:
137
CA 02726300 2010-12-22
H cc I \ \O
H 0 H
O 0 / N 0 S 0
H
H
NHZ N9c>9Q9~ccpcx0
H
~ \ \ N\ \ \ N II
/ O O O 00
and R29 is selected from the group consisting of hydrogen, or Ci - C3 alkyl,
X2 is N and R3' and R32 are independently selected from Hydrogen
[02971 Another even more especially preferred embodiment of the invention
provides
compounds having the following structures. or a salt, hydrate, solvate, N-
oxide, or a
derivative thereof which is a prodrug wherein:
138
CA 02726300 2010-12-22
p PQ N I\ N
: O> / S 0 O
EN) EN) EN) () `)
\N NJ N
H H H H H H
p p~ (;Q (?::,o / O / O
(N) (N) (N) (N) (N) CN)
H H H H N N
(?~) N 9()9) O ) p p (N) (N)
(N) \N" N N N H H H H H
H
9:) NH2 q p p O O 0 0
N1 (() ()
(N) (N) (N) NN N N
H I I H I H
[02981 Another even more preferred embodiment of the invention provides
compounds
having structural Formula (V) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
R28 is of the formula below:
S2
N
S1_ >=O
Z
Where S' is hydrogen, halogen, CN, CF3, 0 CF3, S CF3, C1- C3 alkoxy, animo,
NR3R4 where R3 and R4 are as defined above
and S2 is selected from hydrogen or C1 - C3 alkyl;
Z is CH2, NH, S, SO, SO2 or 0
R29 is selected from the group consisting of hydrogen, C1- C3 alkyl, or
substituted C1
- C3 alkyl,
X2 is N and R31 and R32 are independently selected from Hydrogen or methyl.
139
CA 02726300 2010-12-22
10299] Another especially preferred embodiment of the invention provides
compounds
having structural Formula (V) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
R28 is of the formula below:
S2
N
S1 >=O
Z
Where S' is hydrogen, halogen, CN, CF3, 0 CF3, S CF3, C, - C3 alkoxy, animo,
NR3R4 where R3 and R4 are as defined above
and S2 is selected from hydrogen or C1- C3 alkyl;
Z is CH2, or 0
R29 is selected from the group consisting of hydrogen, C1- C3 alkyl, or
substituted C,
- C3 alkyl,
X2 is N and R31 and R32 are independently selected from Hydrogen or methyl.
[03001 Another even more especially preferred embodiment of the invention
provides
compounds having the following structures. or a salt, hydrate, solvate, N-
oxide, or a
derivative thereof which is a prodrug wherein:
9I>=o ~ 0/ ~ N 00 9ti>=o
EN) CND ()
N EN) N
J
[03011 Another more preferred embodiment of the invention provides compounds
having
structural Formula (V) shown above or a salt, hydrate, solvate or N-oxide
thereof or a
derivative thereof which is a prodrug wherein:
R28 is selected from the group consisting of aryl, substituted aryl,
heteroaryl, or
substituted heteroaryl;
and R29 is a substituted alkyl group of the following formula (t) below:
-~ CH2 )X3-Ar'
(t)
Where as is an integer from 1 to 5
140
CA 02726300 2010-12-22
X3 is CH2, CR3R4, CO, or S(O)b,
b=0,1,or2
R3-R4 are independently selected from the group consisting of hydrogen, C1-C6
alkyl,
substituted C1-C6 alkyl, aryl, substituted aryl, C1-C6 heteroalkyl,
substituted C1-C6
heteroalkyl, , C3 - C7 cycloalkyl or alternatively R3 and R4, together with
the atoms to which
they are bonded form a cycloalkyl, cycloheteroalkyl ring;
Ar' is an alkyl group or phenyl ring optionally substituted with one to five
groups
selected from hydrogen, halogen, C1-C6 alkyl, C3 - C7 cycloalkyl, hydroxyl,
azido, CN,
NO2, OR3, NR3R4 , C02R 3, CO NR3R4 where R3 and R4 are as described above.
X2 is N and
R31 and R32 are independently selected from Hydrogen or C, - C3 alkyl. In some
examples, one R31 or R32 is hydrogen and the other R31 or R32 together with X2
when X2 is C
can form a carbon carbon double bond.
103021 Another even more preferred embodiment of the invention provides
compounds
having structural Formula (V) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
R28 is selected from the group consisting of aryl, substituted aryl,
heteroaryl, or
substituted heteroaryl;
and R29 is a substituted alkyl group of the following formula (t):
-( CHZ )X3-Ar1
(t)
Where as is an integer from 1 to 5
X3 is CH2, CR3R4, CO, or S(O)b,
b=0,1,or2
R3-R4 are independently selected from the group consisting of hydrogen, C1-C6
alkyl,
substituted C1-C6 alkyl, aryl, substituted aryl, C1-C6 heteroalkyl,
substituted C1-C6
heteroalkyl, , C3 - C7 cycloalkyl or alternatively R3 and R4, together with
the atoms to which
they are bonded form a cycloalkyl, cycloheteroalkyl ring;
Arl is an alkyl group or a phenyl ring optionally substituted with one to five
groups
selected from hydrogen, halogen, C1-C6 alkyl, C3 - C7 cycloalkyl, hydroxyl,
azido, CN,
NO2, OR3, NR3R4 , CO2R3, CO NR3R4 where R3 and R4 are as described above.
X2 is N and
R31 and R32 are independently selected from Hydrogen or C, - C3 alkyl.
141
CA 02726300 2010-12-22
[03031 Another especially preferred embodiment of the invention provides
compounds
having structural Formula (V) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
R28 is selected from the group consisting of aryl, substituted aryl,
heteroaryl, or
substituted heteroaryl;
and R29 is a substituted alkyl group of the following formula (t):
-(CH2 )X3-Ar1
(t)
Where as is an integer from 2 to 4
X3 is CO, or S(O)b,
Where b is 2
Arl is an alkyl group or a phenyl ring optionally substituted with one to five
groups
selected from hydrogen, halogen, C,-C6 alkyl, C3 - C7 cycloalkyl, hydroxyl,
azido, CN,
NO2, OR3, where R3 is as described above.
X2 is N and
R31 and R32 are independently selected from Hydrogen or C1 - C3 alkyl.
[03041 Another even more especially preferred embodiment of the invention
provides
compounds shown below or a salt, hydrate, solvate or N-oxide thereof or a
derivative thereof
which is a prodrug:
142
CA 02726300 2010-12-22
r
0 N I r
N-_ N~ O,,~OH 0 I IN \ 0
H NO,-,J,,OH
F I H
F
0 ~N I r
r I H0 0 N \ 0
N~~N~ O
F HO0 ,\-,'O H
/-Z
F / \ HN~~ UN 0 NH N i
0
0 O / , 0 0
0 OH OH
F
e H ON
N~
&N
F H ON
j= N F
HO HN
r N=N
O rN I O r I
NO J OH 0 JN
H \ 0
HO~,OH
r
0 r I r
N
O
all N H~ N~ O J OH NH rN 0
H~ 'NJ O~,OH
_,j O O 0, S N N0
P-
H N~ OOH
F all H
0 rN I F Cr H~~~/ 0 r I N 0-
\/ H
F
r I
0 \ O 0 -IrN
O
F HN~ 0~ \ I N----' N~ O OH
F
143
CA 02726300 2010-12-22
Op N \ O ~~S ~~N J O,_,~,OH
N~,N J OOH H
H
0,0 N O
0 rN L O ~sl
~~ N O J H
N
H
\ I ~/
N N~\N
\
0
H H N
am' I
HN
N,N
[03051 Another more preferred embodiment of the invention provides compounds
having
structural Formula (V) shown above or a salt, hydrate, solvate or N-oxide
thereof or a
derivative thereof which is a prodrug wherein:
R28 is of the formula (e) below;
N
S
(O)q
(e)
Where g is 0, 1, or 2
X2 is selected from N or CH and R31 and R32 are independently selected from
Hydrogen or C1 - C3 alkyl. In some examples, one R31 or R32 is hydrogen and
the other R31
or R32 together with X2 when X2 is C can form a carbon carbon double bond.
and R29 is a substituted alkyl group of the following formula (u) below:
-~CH2 )X3-Ar2
(u)
Where as is an integer from 1 to 5
X3 is CH2, CR3R4, CO, or S(O)b,
b=0,1,or2
R3-R4 are independently selected from the group consisting of hydrogen, C1-C6
alkyl,
substituted C1-C6 alkyl, aryl, substituted aryl, C1-C6 heteroalkyl,
substituted C1-C6
144
CA 02726300 2010-12-22
heteroalkyl, , C3 - C7 cycloalkyl or alternatively R3 and R4, together with
the atoms to which
they are bonded form a cycloalkyl, cycloheteroalkyl ring;
Ar 2 is an aryl or heteroaryl ring optionally substituted with one to five
groups selected
from hydrogen, halogen, C1-C6 alkyl, C3 - C7 cycloalkyl, hydroxyl, azido, CN,
NO2, OR3,
NR3R4 , C02R3, CO NR3R4 where R3 and R4 are as described above.
[03061 Another even more preferred embodiment of the invention provides
compounds
having structural Formula (V) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
R28 is of the formula (e) below;
N
~ S
(O)q
(e)
Where g is 0, 1, or 2
X2 is N and R3' and R32 are independently selected from Hydrogen or C1 - C3
alkyl.
and R29 is a substituted alkyl group of the following formula (u) below:
-( CH2 )X3-Ar2
(u)
Where as is an integer from 1 to 5
X3is CH2, CR3R4, CO, or S(O)b,
b = 0,1, or 2
R3-R4 are independently selected from the group consisting of hydrogen, C1-C6
alkyl,
substituted C1-C6 alkyl, aryl, substituted aryl, C1-C6 heteroalkyl,
substituted C1-C6
heteroalkyl, , C3 - C7 cycloalkyl or alternatively R3 and R4, together with
the atoms to which
they are bonded form a cycloalkyl, cycloheteroalkyl ring;
Ar2 is an aryl or heteroaryl ring optionally substituted with one to five
groups selected
from hydrogen, halogen, C1-C6 alkyl, C3 - C7 cycloalkyl, hydroxyl, azido, CN,
NO2, OR3,
NR3R4 , C02R3, CO NR3R4 where R3 and R4 are as described above.
[03071 Another even more preferred embodiment of the invention provides
compounds
having structural Formula (V) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
145
CA 02726300 2010-12-22
R28 is of the formula (e) below;
(O)q
(e)
Where gis0, 1,or2
X2 is N and R31 and R32 are independently selected from Hydrogen or C1 - C3
alkyl.
and R29 is a substituted alkyl group of the following formula (u) below:
-(CH2 J as X3-Ar2
(u)
Where as is 1 or 3
X3 is CH2,
Ar2 is an aryl or heteroaryl ring optionally substituted with one to five
groups selected
from hydrogen, halogen, C1-C6 alkyl, C3 - C7 cycloalkyl, hydroxyl, azido, CN,
NO2, OR3,
NR3R4 , C02R 3, CO NR3R4 where R3 and R4 are as described above.
103081 Another especially preferred embodiment of the invention provides
compounds
having structural Formula (V) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
R28 is of the formula (e) above;
Where g is 0, 1, or 2
X2 is N and R31 and R32 are independently selected from Hydrogen or C1- C3
alkyl.
and R29 is a substituted alkyl group of the following formula (u) above:
Where as is 1 or 3
X3 is CH2,
Ar2 is selected from the following radicals:
146
CA 02726300 2010-12-22
N
)1N N
V-(): I I N OH \ i /
/ I N \---W/
H H O O\
S / N
O / N~O , i~NH2 I N//
)J/>_NH2 N N N
H H H
N N
S p N}-NH2 \ / N
O O
N
H H H
H H
NJ S N ~( \ N -0 XXo N
OH
optionally substituted with one to five groups selected from hydrogen,
halogen, C1-
C3 alkyl, C3 - C7 cycloalkyl, phenyl, hydroxyl, azido, CN, NO2, OR3, NR3R4 ,
CO2R3, CO
NR3R4 where R3 and R4 are as described above.
[03091 Another even more especially preferred embodiment of the invention
provides
compounds shown below or a salt, hydrate, solvate or N-oxide thereof or a
derivative thereof
which is a prodrug:
N CI N _N
N \ I'-J O
tiN e0 N ~. J --o
NUJ
S-N S-N S--N
H H
Q
~s j',N N
>=o
N O N IE~0 N N Q
W, NH
S-N S--N S N
147
CA 02726300 2010-12-22
r`. S N
NN N "~S ( IN
N
vN~ N S-N
S--N S- N H
S r N N
^`yf ,-NH2 -NH2 N
N ti' N N ~~ S r'`- N
YN N, Nom.
SN S`N S"N
O N
S S-N
[0310] Another more preferred embodiment of the invention provides compounds
having
structural Formula (VI) shown below or a salt, hydrate, solvate or N-oxide
thereof or a
derivative thereof which is a prodrug wherein:
R31
3 "Res
xt't'
R28' r N R32
VI
R28 is selected from the group consisting of aryl, substituted aryl,
heteroaryl, or
substituted heteroaryl;
and R29 are independently selected from the group consisting of alkyl
substituted
alkyl, alkylaryl, substituted alkylaryl, alkoxyaryl, substituted alkoxyaryl,
aryl, substituted
aryl, heteroaryl, and substituted heteroaryl,
X3 is selected from N or C or CR33 where R33 is hydrogen, hydroxyl or C1-C3
alkyl
and R31 and R32 are independently selected from Hydrogen or C1 - C3 alkyl. In
some
examples, one R31 or R32 is hydrogen and the other R31 or R32 together with X3
when X3 is C
can form a carbon carbon double bond.
[0311] Another even more preferred embodiment of the invention provides
compounds
having structural Formula (VI) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
R28 is selected from the following radicals:
148
CA 02726300 2010-12-22
~ o cl I \ o Cl ~ o off ~ Cl
/ o / o I/ o I/ o I/ O o
J
F O B,~ O
~ ~ I/ o/ s
0
911 S O
y,O) 0 0 0
and R29 are independently selected from the group consisting of alkyl
substituted
alkyl, alkylaryl, substituted alkylaryl, alkoxyaryl, substituted alkoxyaryl,
aryl, substituted
aryl, heteroaryl, and substituted heteroaryl,
X3 is selected from N or C or CR33 where R33 is hydrogen, hydroxyl or CI-C3
alkyl
and R31 and R32 are independently selected from Hydrogen or CI - C3 alkyl. In
some
examples, one R31 or R32 is hydrogen and the other R31 or R32 together with X3
when X3 is C
can form a carbon carbon double bond.
[0312) Another especially preferred embodiment of the invention provides
compounds
having structural Formula (VI) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
R28 is selected from the following radicals:
\ 0 cl I \ 0 CI OfoH CI '
o I/ O / O
/ o 0
F O B, ~ O 0 CI
/ ~/ O o S S
O
(?1"0 I~ S q00
0
and R29 is selected from the following radicals:
149
CA 02726300 2010-12-22
Fl,~
14
OH OH OH OH
I/ iO I j \ I j I I Q
Oz
N OH OH
OzN /
X3 is selected from N or C or CR33 where R33 is hydrogen, hydroxyl or C1-C3
alkyl
and R31 and R32 are independently selected from Hydrogen or C1- C3 alkyl. In
some
examples, one R31 or R32 is hydrogen and the other R31 or R32 together with X3
when X3 is C
can form a carbon carbon double bond.
103131 Another even more especially preferred embodiment of the invention
provides
compounds shown below or a salt, hydrate, solvate or N-oxide thereof or a
derivative thereof
which is a prodrug:
NN \ I 'O I / NT-/N \ I
U 0 0 0 1
OH OH OH
NUN \ / / NUN \ / O j1-NJN--c /
O N ` / NN \ / I NN \ / F I / N~ JN
2
OH OH OH
F
NN \ / I NN \ / ID6- N \ I
OzN / F
U
- \ - OH OH OH OH
- \ - OH
C6 - N
150
CA 02726300 2010-12-22
103141 Another more preferred embodiment of the invention provides compounds
having
structural Formula (VI) shown above or a salt, hydrate, solvate or N-oxide
thereof or a
derivative thereof which is a prodrug wherein:
R28 is selected from the group consisting of aryl, substituted aryl,
heteroaryl, or
substituted heteroaryl;
and R29 are independently selected from the group consisting of alkyl
substituted
alkyl, alkylaryl, and substituted alkylaryl,
X3 is selected from N or C or CR33 where R33 is hydrogen, hydroxyl or C1-C3
alkyl
and R31 and R32 are independently selected from Hydrogen or C1 - C3 alkyl. In
some
examples, one R31 or R32 is hydrogen and the other R31 or R32 together with X3
when X3 is C
can form a carbon carbon double bond.
[03151 Another even more preferred embodiment of the invention provides
compounds
having structural Formula (VI) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
R28 is selected from the group consisting of aryl, substituted aryl,
heteroaryl, or
substituted heteroaryl;
and R29 are independently selected from the group consisting of alkyl
substituted
alkyl, alkylaryl, and substituted alkylaryl,
X3 is N and R31 and R32 are independently selected from Hydrogen or C1 - C3
alkyl.
[0316) Another especially preferred embodiment of the invention provides
compounds
having structural Formula (VI) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
R28 is selected from the following radicals:
90 VO) Pc,
CF3 CN I OH 0'-'-/ I Off/
and R29 are independently selected from the group consisting substituted
alkyl,
alkylaryl, and substituted alkylaryl,
X3 is N and R3' and R32 are independently selected from Hydrogen or C1 - C3
alkyl.
151
CA 02726300 2010-12-22
103171 Another even more especially preferred embodiment of the invention
provides
compounds having structural Formula (VI) shown above or a salt, hydrate,
solvate or N-oxide
thereof or a derivative thereof which is a prodrug wherein:
R28 is selected from the following radicals:
o~
90 ~0) YICI
CF3 I / CN I ; OH 0", I Off/
and R29 is selected from the following radicals:
O O O N
N I N N
O O
`4z j a----
/ N
O
N
O
X3 is N and Rai and R32 are independently selected from Hydrogen or methyl.
103181 Another even more especially preferred embodiment of the invention
provides
compounds shown below or a salt, hydrate, solvate or N-oxide thereof or a
derivative thereof
which is a prodrug:
152
CA 02726300 2010-12-22
O
O N
O N N O N N
N,) / I \
0 0
\
0 ('N N 0 NJ I / NOJ
NJ / \
0
O N \ N ~\O N I j N
\ NJ /
O r N N NJ /\0 r N 0 NJ
\ / N
/ \ 0
O
0
O ^N N ~O ~N I j N
\ NJ I\
0 ~ 0
0 JO N
N)
NJ / ~ \
0
'~1 Jo rjN 0 ~J N
O
0
~O N N
\ NJ /
[0319] Another more preferred embodiment of the invention provides compounds
having
structural Formula (VII) shown below or a salt, hydrate, solvate or N-oxide
thereof or a
derivative thereof which is a prodrug wherein:
153
CA 02726300 2010-12-22
R34
\
X4
N
(R12)P >=O
N
R33
VII
Where each R12 is independently selected from Hydrogen, halogen, C1-C4 alkyl,
hydroxyl, azido, CN, NO2, OR3, NR3R4 , CO2R3, CO NR3R4 where R3 and R4 are as
described above and p is 0 or an integer from 1-4;
R33 is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6
alkenyl, or
C2-C6 alkynyl
X4 is -CO-, -CONH- or absent,
and R34 is a substituted alkyl group of the following formula (v) below:
R34
\
X4
(R 12)p >==0
N
R33
(v)
Where bb is 2 - 5
And Ar 3 is an aryl or heteroaryl ring optionally substituted with one to five
groups
selected from hydrogen, halogen, CF3, C1-C4 alkyl, C3 - C7 cycloalkyl,
hydroxyl, azido, CN,
NO2, OR3, NR3R4 , CO2R3, CO NR3R4 where R3 and R4 are as described above.
[03201 Yet another even more preferred embodiment of the invention provides
compounds having structural Formula (VII) shown above or a salt, hydrate,
solvate or
N-oxide thereof or a derivative thereof which is a prodrug wherein:
Where each R12 is independently selected from Hydrogen, halogen, C1-C4 alkyl,
hydroxyl, azido, CN, NO2, OR3, NR3R4 , CO2R3, CO NR3R4 where R3 and R4 are as
described above and p is 0 or an integer from 1-4;
R33 is selected from the group consisting of hydrogen, C I -C4 alkyl
X4 is absent,
and R34 is a substituted alkyl group of the following formula (v) below:
HCH2N N-Ar3
(v)
154
CA 02726300 2010-12-22
Wherebbis2-5
And Ar-a is an aryl or heteroaryl ring optionally substituted with one to five
groups
selected from hydrogen, halogen, CF3, C1-C4 alkyl, C3 - C7 cycloalkyl,
hydroxyl, azido, CN,
NO2, OR3, NR3R4 , CO2R3, CO NR3R4 where R3 and R4 are as described above.
[0321] Yet another especially preferred embodiment of the invention provides
compounds
having structural Formula (VII) shown above or a salt, hydrate, solvate or N-
oxide thereof or
a derivative thereof which is a prodrug wherein:
Where each R12 is independently selected from Hydrogen, halogen, C1-C4 alkyl,
hydroxyl, azido, CN, NO2, OR3, NR3R4 , C02R3, CO NR3R4 where R3 and R4 are as
described above and p is 0 or an integer from 1-2;
R33 is selected from the group consisting of hydrogen, C1-C4 alkyl
X4 is absent,
and R34 is a substituted alkyl group of the following formula (v) below:
HCH2 bN 'N-Ar3
(v)
Where bb is 2 - 4
And Ar 3 is an aryl or heteroaryl ring optionally substituted with one to five
groups
selected from hydrogen, halogen, CF3 , C1-C4 alkyl, C3 - C7 cycloalkyl,
hydroxyl, azido, CN,
NO2, OR3, NR3R4 , C02R 3, CO NR3R4 where R3 and R4 are as described above.
[0322] Another even more especially preferred embodiment of the invention
provides
compounds shown below or a salt, hydrate, solvate or N-oxide thereof or a
derivative thereof
which is a prodrug:
155
CA 02726300 2010-12-22
O 0
HN~ CF3 HN4 N/--\ CI
N-_N N N~_ N
~0 CI 0 CF3
HN N HN N
N / N~ ~N /
N
~/O , ~/~ NCF3 /~O CN
CF N N 3
QI-- CF3 0 0 N N4 N N CF3
HN-~ N,/ N /
N-/
0 CF3
O HN4 N
HN4 /'' NN
o
[03231 Another more preferred embodiment of the invention provides compounds
having
structural Formula (VIII) shown below or a salt, hydrate, solvate or N-oxide
thereof or a
derivative thereof which is a prodrug wherein:
R31
NR38
'][::::)Y ? R37 H
R35 N
R36 N R32 12)
0
VIII
Where each R12 is independently selected from Hydrogen, halogen, CI-C4 alkyl,
hydroxyl, azido, CN, NO2, OR3, NR3R4 , C02R3, CO NR3R4 where R3 and R4 are as
described above and p is 0 or an integer from 1-3;
R35 and R36 are independently selected from the group consisting of hydrogen,
or
halogen,
156
CA 02726300 2010-12-22
R31 and R32 are as defined above
R37 is selected from Hydrogen, hydroxyl or halogen
And R38 is selected from Hydrogen, halogen, C1-C5 alkyl, substituted C1-C5
alkyl, C3-
C5 cycloalkyl, aryl, heteroaryl, OR3, or NR3R4 , where R3 and R4 are as
described above.
[0324] Another even more preferred embodiment of the invention provides
compounds
having structural Formula (VIII) shown above or a salt, hydrate, solvate or N-
oxide thereof or
a derivative thereof which is a prodrug wherein:
Where each R12 is independently selected from Hydrogen, halogen, C1-C4 alkyl,
hydroxyl, azido, CN, NO2, OR3, NR3R4 , C02R3, CO NR3R4 where R3 and R4 are as
described above and p is 0 or an integer from 1-3;
R35 and R36 are either both hydrogen or represent the following substitutions;
3,4-
dichloro, 3, chloror-4-flouro,
R31 and R32 are hydrogen
R37 is selected from Hydrogen, hydroxyl or flouro
And R38 is selected from Hydrogen, halogen, C1-C5 alkyl, substituted C1-C5
alkyl, C3-
C5 cycloalkyl, aryl, heteroaryl, OR3, or NR3R4 , where R3 and R4 are as
described above.
103251 Another especially preferred embodiment of the invention provides
compounds
having structural Formula (VIII) shown above or a salt, hydrate, solvate or N-
oxide thereof or
a derivative thereof which is a prodrug wherein:
Where each R12 is independently selected from Hydrogen, halogen, C1-C4 alkyl,
hydroxyl, azido, CN, NO2, OR3, NR3R4 , CO2R3, CO NR3R4 where R3 and R4 are as
described above and p is 0 or an integer from 1-3;
R35 and R36 are either both hydrogen or represent the following substitutions;
3,4-
dichloro, 3, chloror-4-flouro,
R31 and R32 are hydrogen
R37 is selected from Hydrogen, hydroxyl or flouro
And R38 is selected from the following radicals:
157
CA 02726300 2010-12-22
(N' N\ N- N A
N N-j N=N
Nl~
CI N OWN
Nl~
i C Ji _ N
O c c
CF3 F
NHS
[03261 Another even more especially preferred embodiment of the invention
provides
compounds shown below or a salt, hydrate, solvate or N-oxide thereof or a
derivative thereof
which is a prodrug:
0 0 0
CI
1..~`<,~f..~;:~-,.~,,~ `,~) I,~1~~.~'~ '.=, it T,;lrCt ~-~'~~'--~ '~'````~F
0 0
'CI CI
I I I
158
CA 02726300 2010-12-22
0 0 0
H ".` Nr H N CI
N N." N,. N .~'`',.CI N N'~tiz~'Hd..,~ ti.F
0 0
H H H
N'. HN .-N. .4~N-' "cI HN N' `-, Nõ .-~= ` F
0 0
~.. -N N' C! N ,.c
H H H j
~j 4 1 Nl s ;i r ? N vl. v r~ CI ~.~ N N ~= i, F
9 0 k-- o 0 0 0
,CI CI
0
N~ 0 0 N 0 CI N'
Nk a I , .. N, .. r .Cl
,H
N-^.. N.,~ N CI N. N N F
N 0 0 0
N CI N,. 'a
N N. N N ,,r.~. r., / `'r,l N F F 0 I 0 F I 0
N N A CI N Ct
,N F .N ft. ,r - .C .., F
F F
0 0 0
...,,,.: rr-'<.'ti - . . ~;,., .= N ,~, w,, r.~y; Pf'.) ~,, s',.. ~ N,-"~. /:~-
~- ail
>~. H } r 1 H
H`N N M F.,r H.N N N F CI HEN. N N F
[03271 Another more preferred embodiment of the invention provides compounds
having
structural Formula (IX) shown below or a salt, hydrate, solvate or N-oxide
thereof or a
derivative thereof which is a prodrug wherein:
Ras
N"
F3C
IX
Where R39 is of the following formula (w) below:
-(CH2JC Ar4
(w)
Where cc is an integer from 1 to 5 and Ar4 is an aryl, substituted aryl,
heteroaryl or
substituted heteroaryl
159
CA 02726300 2010-12-22
103281 Another even more preferred embodiment of the invention provides
compounds
having structural Formula (IX) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
Where R39 is of the following formula (w) below:
-( CH )-r4
(w)
Where cc is 2 and Ar4 is an aryl, substituted aryl, heteroaryl or substituted
heteroaryl
103291 Another especially preferred embodiment of the invention provides
compounds
having structural Formula (IX) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
Where R39 is of the following formula (w) below:
-l CHZ ACC Ar4
(w)
Where cc is 2 and Ar4 is a substituted or unsubstituted pyridyl or naphthalene
ring.
103301 Another even more especially preferred embodiment of the invention
provides
compounds shown below or a salt, hydrate, solvate or N-oxide thereof or a
derivative thereof
which is a prodrug:
N N N
n-J
F3C I \ \N N N F3C I \ \ F3Ci I \ \
N~z
N N N N
F3C F3C \ \ \ I F3C
103311 Another even more preferred embodiment of the invention provides
compounds
having structural Formula (X) shown below or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
R41
(R42)Z i \ \
~ N
Roo
160
CA 02726300 2010-12-22
x
Where R40 is selected from hydrogen or C1-C3 alkyl
And R41 is selected from C1-C6 alkyl, substituted C1-C6 alkyl, C3-C8
cycloalkyl, C3-C8
cycloheteroalkyl, C3-C8 cycloalkenyl, or C3-C8 cycloheteroalkenyl.
and each R42 is independently selected from Hydrogen, halogen, C1-C4 alkyl,
hydroxyl, azido, CN, NO2, OR3, NR3R4 , C02R3, CO NR3R4 where R3 and R4 are as
described above and z is 0 or an integer from 1-4;
(03321 Another especially preferred embodiment of the invention provides
compounds
having structural Formula (X) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
Where R40 is selected from hydrogen or C1-C3 alkyl
And R41 is selected from C1-C6 alkyl, substituted C1-C6 alkyl, C3-C8
cycloalkyl, C3-C8
cycloheteroalkyl, C3-C8 cycloalkenyl, or C3-C8 cycloheteroalkenyl.
and each R42 is independently selected from Hydrogen, halogen, C1-C4 alkyl,
hydroxyl, CN, OR3, NR3R4 , CO2R3, CO NR3R4 where R3 and R4 are as described
above and
z is 0 or an integer from 1-2;
103331 Another even more especially preferred embodiment of the invention
provides
compounds shown below or a salt, hydrate, solvate or N-oxide thereof or a
derivative thereof
which is a prodrug:
161
CA 02726300 2010-12-22
-O -O 'O 'O
NH NH NH NH
N N N N
H H / /
NH2 / NH2 / NH2 / NH2
/N N N N N
H H / /
~p -O
H2N 0 H2N
NI- N, NH NH2
H N
H H
H
N p
\
N H2N O H2N
NH
NH N-,
N- ~
N
N H H O H O H H
~N ~N HO
NH
/ NH2 / NH2 NH2
H
H H H N
HO
CI CI CI
NH NH NH2
NH2
H
H H H
HO
NH NH NH2
NH2
H I _ N H H
N
H
HO
NH
N
H
103341 Another more preferred embodiment of the invention provides compounds
having
structural Formula (X) shown below or a salt, hydrate, solvate or N-oxide
thereof or a
derivative thereof which is a prodrug wherein:
162
CA 02726300 2010-12-22
0
R44-(CH2)dd /--\ N-(CH2)ee'NN-R43
R42
X
Where R44 is selected from C1-C12 alkyl, substituted C1-C12 alkyl, C3-C12
cycloalkyl,
C3-C12 cycloheteroalkyl, C3-C12 cycloalkenyl, or C3-C12 cycloheteroalkenyl,
aryl, substituted
aryl, heteroaryl or substituted heteroaryl;.
dd is 0 or 1,
Where R42 is selected from hydrogen and C1-C3 alkyl
ee is an integer from 2 - 5
and R43 is selected from aryl, substituted aryl, heteroaryl or substituted
heteroaryl;.
103351 Another even more preferred embodiment of the invention provides
compounds
having structural Formula (X) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
Where R44 is selected from C1-C12 alkyl, substituted C1-C12 alkyl, C3-C12
cycloalkyl,
C3-C12 cycloheteroalkyl, C3-C12 cycloalkenyl, or C3-C12 cycloheteroalkenyl,
aryl, substituted
aryl, heteroaryl or substituted heteroaryl;.
dd is 0 or 1,
Where R42 is selected from hydrogen and C1-C3 alkyl
ee is an integer from 2 - 5
and R43 is of the formula (d) below
N J (R9)0
N
(d)
Where each R9 is independently selected from Hydrogen, halogen, C1-C3 alkyl,
or
triflouromethyl and o is 0 or an integer from 1-3;
[03361 Another especially preferred embodiment of the invention provides
compounds
having structural Formula (X) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
Where R44 is selected from the following radicals:
163
CA 02726300 2010-12-22
(R45) (R45)xx\ (R45)x, > (R45)xx
-;:-,]::o >
H O
H
Where R45 is selected from hydrogen, halogen, C1-C3 alkyl, or C1-C3 alkoxy,
and xx is
an integer from 1 to 3.
dd is 0 or 1,
Where R42 is selected from hydrogen and C1-C3 alkyl
ee is an integer from 2 or 3
and R43 is of the formula (d) below
(R9)0
N
(d)
Where each R9 is independently selected from Hydrogen, halogen, C1-C3 alkyl,
or
triflouromethyl and o is 0 or an integer from 1-3;
103371 Another even more especially preferred embodiment of the invention
provides
compounds shown below or a salt, hydrate, solvate or N-oxide thereof or a
derivative thereof
which is a prodrug:
164
CA 02726300 2010-12-22
OO O
-4
HN--~_ ~N HN~_NN~ND HN-\_N
O O / I Q~-~\ O D
HN~NN HN- ~ N- \ O HNN NN
\J ~NN\~N~\ N NNH NH NH
O N N) O NCNN) O JNN)
N N N
,A- O
O NH
N:) HN~NN-/\ O N\ N-
N N-~\ N D/
N N
~O
HN-\_ N NH
NN-/\\ :/~-F 0 /--\ N7~/-F
N N~~N-<\ N
[03381 Another more preferred embodiment of the invention provides compounds
having
structural Formula (XI) shown below or a salt, hydrate, solvate or N-oxide
thereof or a
derivative thereof which is a prodrug wherein:
0
R48
N
R47 ~--N NR45
R46
XI
Where R45 is selected from aryl, substituted aryl, heteroaryl or substituted
heteroaryl;
R46 is selected from hydrogen or Cl-C3 alkyl
R47 is selected from aryl, heteroaryl cycloalkyl or cycloheteroalkyl
and R48 is selected from aryl, substituted aryl, heteroaryl substituted
heteroaryl,
cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted
cycloheteroalkyl.
103391 Another even more preferred embodiment of the invention provides
compounds
having structural Formula (XI) shown below or a salt, hydrate, solvate or N-
oxide thereof or
a derivative thereof which is a prodrug wherein:
165
CA 02726300 2010-12-22
R484O
N f-~
R47 > --N N-R45
R46
XI
Where R45 is selected from the following radicals:
b(Zbc I \ O~ OI \ \
I \ / / N
H
R46 is selected from hydrogen or C1-C3 alkyl
R47 is selected from aryl, heteroaryl cycloalkyl or cycloheteroalkyl
and R48 is selected from aryl, substituted aryl, heteroaryl substituted
heteroaryl,
cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted
cycloheteroalkyl.
[0340] Another especially preferred embodiment of the invention provides
compounds
having structural Formula (XI) shown above or a salt, hydrate, solvate or N-
oxide thereof or a
derivative thereof which is a prodrug wherein:
Where R45 is selected from the following radicals:
/ J / J C)O - - N
O S H
R46 is selected from hydrogen or C1-C3 alkyl
R47 is selected from the following radicals:
N
6EN
and R48 is selected from aryl, substituted aryl, heteroaryl substituted
heteroaryl,
cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted
cycloheteroalkyl.
[0341] Another even more especially preferred embodiment of the invention
provides
compounds shown below or a salt, hydrate, solvate or N-oxide thereof or a
derivative thereof
which is a prodrug:
166
CA 02726300 2010-12-22
N N
N N O a-N N O a,,
N N 0 N N N N O
Y Y Y Y Y
N () ~N) EN) EN) EN)
N N N N N
nN dE )
H H 0 0
103421 Another more preferred embodiment of the invention provides compounds
having
structural Formula (XII) shown below or a salt, hydrate, solvate or N-oxide
thereof or a
derivative thereof which is a prodrug wherein:
HNANJ
N`R49
HN
R50
XII
Where R49 is selected from hydrogen or C1-C6 alkyl
R50 is selected from hydrogen or halogen
And the dashed line represents either a single or double bond
103431 Another even more preferred embodiment of the invention provides
compounds
having structural Formula (XII) shown above or a salt, hydrate, solvate or N-
oxide thereof or
a derivative thereof which is a prodrug wherein:
Where R49 is selected from hydrogen or C1-C6 alkyl
R50 is selected from chlorine, bromine or iodine
And the dashed line represents either a single or double bond
167
CA 02726300 2010-12-22
103441 Another especially preferred embodiment of the invention provides
compounds
having structural Formula (XII) shown above or a salt, hydrate, solvate or N-
oxide thereof or
a derivative thereof which is a prodrug wherein:
Where R49 is selected from C1-C6 alkyl
R50 is selected from chlorine, bromine or iodine
And the dashed line represents either a single or double bond
103451 Another even more especially preferred embodiment of the invention
provides
compounds shown below or a salt, hydrate, solvate or N-oxide thereof or a
derivative thereof
which is a prodrug:
HNAN" HNANJ HNANJ HNAN" HNAN" HN)II N"
N\ \ I N fHN/ \ N N\ N\
HN HN / HN ( HN HN
CI Br CI Br CI Br
HN'N HNN
VNINHN
CI Br
103461 Another more preferred embodiment of the invention provides compounds
having
structural Formula (XIII) shown below or a salt, hydrate, solvate or N-oxide
thereof or a
derivative thereof which is a prodrug wherein:
R51
N~R52
N
R 54
-
Xb/\-- R53
XIII
Where X4 is selected from S, SO, SO2, NH, or NR3 where R3 is as defined above
R51 and R52 are independently selected from the group consisting of hydrogen,
alkyl,
substituted alkyl, heteroalkyl, substituted heteroalkyl, or alternatively, R5'
and R52, together
168
CA 02726300 2010-12-22
with the atoms to which they are bonded form a cycloheteroalkyl or substituted
cycloheteroalkyl ring;
R53 and R54 are independently selected from the group consisting of hydrogen,
halogen, hydroxyl, triflouromethyl, C1-C6 alkyl, substituted C1-C6 alkyl, and
C1-C6 alkoxy.
[0347] Another especially preferred embodiment of the invention provides
compounds
having structural Formula (XIII) shown above or a salt, hydrate, solvate or N-
oxide thereof or
a derivative thereof which is a prodrug wherein:
R51
N, N~R52
R54 L
X4 / \ R53
XIII
Where X4 is selected from S, or NH,
R51 and R52, together with the atoms to which they are bonded form a
cycloheteroalkyl or substituted cycloheteroalkyl ring;
R53 and R54 are independently selected from the group consisting of hydrogen,
halogen, hydroxyl, triflouromethyl, C 1-C6 alkyl, substituted C I -C6 alkyl,
and C 1-C6 alkoxy.
[0348] Another even more especially preferred embodiment of the invention
provides
compounds shown below or a salt, hydrate, solvate or N-oxide thereof or a
derivative thereof
which is a prodrug:
_N rN <-N ~N
N N
N~ NJ )
XD- - ~ N/ \ I / / \ BH S
/'-NH (N) N
N_/ N
N, N CI N- CI N, Br N,
H H
[0349] Another more preferred embodiment of the invention provides compounds
having
structural Formula (XIV) shown below or a salt, hydrate, solvate or N-oxide
thereof or a
derivative thereof which is a prodrug wherein:
169
CA 02726300 2010-12-22
R57 R55
58 1
R N, R56
R59
R60
XIV
R55 and R56 are independently selected from the group consisting of hydrogen,
C1-C6
alkyl, substituted C1-C6 alkyl, C1-C6 heteroalkyl, substituted C1-C6
heteroalkyl, or
alternatively, R51 and R52, together with the atoms to which they are bonded
form a
cycloheteroalkyl or substituted cycloheteroalkyl ring;
R57, R58 , R59 and R60 are independently selected from the group consisting of
hydrogen, halogen, hydroxyl, triflouromethyl, C1-C6 alkyl, substituted C1-C6
alkyl, and C1-C6
alkoxy. In some instances, R57 and R58 together with the atoms to which they
are bound form
an aliphatic or aromatic ring.
103501 Another even more preferred embodiment of the invention provides
compounds
having structural Formula (XIV) shown above or a salt, hydrate, solvate or N-
oxide thereof or
a derivative thereof which is a prodrug wherein:
R55 and R56 are independently selected from the group consisting of hydrogen,
C1-C6
alkyl, substituted C1-C6 alkyl, C1-C6 heteroalkyl, substituted C1-C6
heteroalkyl, or
alternatively, R51 and R52, together with the atoms to which they are bonded
form a
cycloheteroalkyl or substituted cycloheteroalkyl ring;
R57 , R58 and R60 are independently selected from the group consisting of
hydrogen,
halogen, hydroxyl, triflouromethyl, C1-C6 alkyl, substituted C1-C6 alkyl, and
C1-C6 alkoxy.
In some instances, R57 and R58 together with the atoms to which they are bound
form an
aliphatic or aromatic ring.
And R59 is hydrogen
103511 Another especially preferred embodiment of the invention provides
compounds
having structural Formula (XIV) shown above or a salt, hydrate, solvate or N-
oxide thereof or
a derivative thereof which is a prodrug wherein:
R55 and R56 are independently selected from the group consisting of hydrogen,
C1-C4
alkyl, or alternatively, R51 and R52, together with the atoms to which they
are bonded form a
cycloheteroalkyl ring;
R57 , R58 and R60 are independently selected from the group consisting of
hydrogen,
halogen, hydroxyl, triflouromethyl, C1-C6 alkyl, substituted C1-C6 alkyl, and
C1-C6 alkoxy.
170
CA 02726300 2010-12-22
In some instances, R57 and R58 together with the atoms to which they are bound
form an
aliphatic or aromatic ring.
And R59 is hydrogen
[03521 Another even more especially preferred embodiment of the invention
provides
compounds shown below or a salt, hydrate, solvate or N-oxide thereof or a
derivative thereof
which is a prodrug:
OH OH OH OH
N
D N N N
I/
CT
F F
OH r OH (O OH (NH OH (NH
~cJN) I~ NJ ~cI
/
iN N 0N N
1 ~ 1
HN HN
N ,/\ HN N H N
N /N N N
rO rO ~NH ~NH
HN NJ HN NJ HN NJ HN "\NJ
[03531 Another more preferred embodiment of the invention provides compounds
having
structural Formula (XV) shown below or a salt, hydrate, solvate or N-oxide
thereof or a
derivative thereof which is a prodrug wherein:
R62'' N R63
R61
XV
R61 is selected from hydrogen or Ci-C6 alkyl
R63 is selected from the group consisting of alkyl, cycloalkyl, substituted
cycloalkyl,
aryl, substituted aryl, heteroaryl and substituted heteroaryl;
R62 is selected from the group consisting of alkyl, substituted alkyl,
cycloalkyl and
substituted cycloalkyl
171
CA 02726300 2010-12-22
103541 Another even more preferred embodiment of the invention provides
compounds
having structural Formula (XV) shown above or a salt, hydrate, solvate or N-
oxide thereof or
a derivative thereof which is a prodrug wherein:
R61 is selected from hydrogen or CI-C6 alkyl
R63 is selected from the group consisting of aryl, substituted aryl,
heteroaryl and
substituted heteroaryl;
R62 is selected from the following radicals:
cc' / sue`
CI CI
acl CI "Ja aCI
[03551 Another especially preferred embodiment of the invention provides
compounds
having structural Formula (XV) shown above or a salt, hydrate, solvate or N-
oxide thereof or
a derivative thereof which is a prodrug wherein:
R61 is selected from hydrogen or methyl
R63 is selected from the group consisting of aryl, substituted aryl,
heteroaryl and
substituted heteroaryl;
R62 is selected from the following radicals:
ociA sue` I~
c('
I N
CI
c(:'
CI
103561 Another even more especially preferred embodiment of the invention
provides
compounds having structural Formula (XV) shown above or a salt, hydrate,
solvate or
N-oxide thereof or a derivative thereof which is a prodrug wherein:
172
CA 02726300 2010-12-22
R61 is selected from hydrogen or methyl
R63 is selected from the following radicals:
F CI F CI
N N
N N
R62 is selected from the following radicals:
~ CI CI N
O
O
j u I O~
\ p~ I pu I
Ar-
a/
a
CI CI
CI
103571 Another even more especially preferred embodiment of the invention
provides
compounds shown below or a salt, hydrate, solvate or N-oxide thereof or a
derivative thereof
which is a prodrug:
173
CA 02726300 2010-12-22
O
H H
N CF / O
H I I H
N N
F
I
O
OXNOO
I H F F
S~~N / I I O~\H / I \
H N
N F / O\
I
I` H 'I~ p H
CI CI N
p H I \ p\/~ N /
H
N N
[0358] Another even more preferred embodiment of the invention provides
compounds
having structural Formula (XV) shown above or a salt, hydrate, solvate or N-
oxide thereof or
a derivative thereof which is a prodrug wherein:
R61 is selected from hydrogen or C1-C4 alkyl
R63 is selected from the group consisting of alkyl, cycloalkyl, substituted
cycloalkyl,
aryl, substituted aryl, heteroaryl and substituted heteroaryl;
R62 is selected from the group consisting of alkyl, substituted alkyl,
cycloalkyl and
substituted cycloalkyl
[0359] Another even more preferred embodiment of the invention provides
compounds
having structural Formula (XV) shown above or a salt, hydrate, solvate or N-
oxide thereof or
a derivative thereof which is a prodrug wherein:
R61 is selected from hydrogen or C1-C4 alkyl
R63 is selected from the following radicals:
174
CA 02726300 2010-12-22
j OJ 0 0 O'f
OJJ CO'C JJ Cal
C)a
0 OD /- OD Jo ' Jlo
i i / C
0:a
o / o.J; (O)a oo o s
0 C o )a coa Ca
/-o
0 ("0
\ I O 4 O O'A o/ Ja
< ' j , of CO cla Ccr
JJ' - of J J
/ o J J Oj
JJJ t J
N 0,-,,-,,/ Cp
N
And R62 is selected from the group consisting of alkyl, substituted alkyl,
cycloalkyl
and substituted cycloalkyl
[03601 Another even more preferred embodiment of the invention provides
compounds
having structural Formula (XV) shown above or a salt, hydrate, solvate or N-
oxide thereof or
a derivative thereof which is a prodrug wherein:
R61 is selected from hydrogen or C1-C4 alkyl
R63 is selected from the following radicals:
175
CA 02726300 2010-12-22
o OJ o of 0
0 0'-f 0
0 :or
J JJ
~ (&":) :O
/- 0J
0a . '& J
0 0"/4 0 / I 0
0~s 0 0'_'-'e'
"/a Ca
C JJ co)~Y
0~a 0 , u 0
: co
C 0 of 0/-0 0J / 0J
OJ 0
0 0J
N\ ~
N I / O
And R62 is selected from the following radicals:
cc':c I~
~103611 Another even more especially preferred embodiment of the invention
provides
compounds shown below or a salt, hydrate, solvate or N-oxide thereof or a
derivative thereof
which is a prodrug:
176
CA 02726300 2010-12-22
p l O~~N O \O ~~ C p
H o O O H p NO-O
O, I , H O 'b
O ~~ f
O \ ON O CO
p O~~N O
H O H I H I
~
\O Cr H O \p H pl i ?/ p^=~N O
0
O \ I \ O I ~ ~~N
~-H~p O~~N 0 O
C~ O, I p,
O
CO p I ~
CO I O- N O O / O-~~ N -
I O 1 O 6
\N p--'--\ N o \
O H~~O
~ I O
~I
[03621 Another especially preferred embodiment of the invention provides
compounds
having structural Formula (XVI) shown below or a salt, hydrate, solvate or N-
oxide thereof
or a derivative thereof which is a prodrug wherein:
R64
N OH N N NH
N O
O
O
XVI
R64 is selected from hydrogen or C1-C6 alkyl
And the dashed line represents a single or a double bond
177
CA 02726300 2010-12-22
103631 Another even more especially preferred embodiment of the invention
provides
compounds shown below or a salt, hydrate, solvate or N-oxide thereof or a
derivative thereof
which is a prodrug:
OHO H N NH N OHO N NH
N N
O N O I N O
O O
103641 Another preferred embodiment of the invention provides compounds having
structural Formula (XVII) shown below or a salt, hydrate, solvate or N-oxide
thereof or a
derivative thereof which is a prodrug wherein:
S
R68 1,1
N,R65
R66
O R67
XVII
R65 and R66 are independently selected from hydrogen or CI-C6 alkyl
R67 is selected from alkyl, substituted alkyl, cycloalkyl or substituted
cycloalkyl.
R68 is selected from the group consisting of hydrogen, halogen, hydroxyl,
triflouromethyl, cyano, nitro, CI-C6 alkyl, substituted CI-C6 alkyl, and CI-C6
alkoxy.
[03651 Another more preferred embodiment of the invention provides compounds
having
structural Formula (XVII) shown above or a salt, hydrate, solvate or N-oxide
thereof or a
derivative thereof which is a prodrug wherein:
R65 and R66 are independently selected from hydrogen or CI-C6 alkyl
R67 is selected from aryl-CI-C3 alkyl, substituted aryl-CI-C3 alkyl,
cycloalkyl or
substituted cycloalkyl.
R68 is selected from the group consisting of hydrogen, halogen, hydroxyl,
triflouromethyl, cyano, nitro, C 1-C6 alkyl, substituted C 1-C6 alkyl, and C 1-
C6 alkoxy.
[03661 Another even more preferred embodiment of the invention provides
compounds
having structural Formula (XVII) shown above or a salt, hydrate, solvate or N-
oxide thereof
or a derivative thereof which is a prodrug wherein:
178
CA 02726300 2010-12-22
R65 and R66 are independently selected from hydrogen or Ci-C3 alkyl
R67 is selected from the following radicals:
o\ o ~'z I o
0
\,.,o \j :) G
R68 is selected from the group consisting of hydrogen, halogen, hydroxyl,
triflouromethyl, cyano, nitro, C 1-C6 alkyl, substituted C 1-C6 alkyl, and C 1-
C6 alkoxy.
[0367] Another even more especially preferred embodiment of the invention
provides
compounds shown below or a salt, hydrate, solvate or N-oxide thereof or a
derivative thereof
which is a prodrug:
S s s S
s
NH NH I / NH NH
NH
NH NH NH NH
NH O Q 0 0 O
X, 0
0
[0368] Additionally, a 5HTR agent may be a reported 5HT2A/2C receptor
antagonist such
as ketanserin (CAS RN 74050-98-9) or ketanserin tartrate; risperidone;
olanzapine;
adatanserin (CAS RN 127266-56-2); ritanserin (CAS RN 87051-43-2); etoperidone;
nefazodone; deramciclane (CAS RN 120444-71-5); geoden or ziprasidone
hydrochloride
(CAS RN 138982-67-9); zeldox or ziprasidone or ziprasidone hydrochloride; EMD
281014
(7-[4-[2-(4-fluoro-phenyl)-ethyl]-piperazine-l-carbonyl]-1H-indole-3-
carbonitrile HC1);
MDL 100907 or M100907 (CAS RN 139290-65-6); effexor XR (venlafaxine
formulation);
zomaril or iloperidone; quetiapine (CAS RN 111974-69-7) or quetiapine fumarate
(CAS RN
111974-72-2) or seroquel; SB 228357 or SB 243213 (see Bromidge et al.
"Biarylcarbamoylindolines are novel and selective 5-HT(2C) receptor inverse
agonists:
identification of 5-methyl-l-[[2-[(2-methyl-3-pyridyl)oxy]- 5-
pyridyl]carbamoyl]-6-
trifluoromethylindoline (SB-243213) as a potential antidepressant/anxiolytic
agent." J Med
Chem. 2000 43(6):1123-34); SB 220453 or tonabersat (CAS RN 175013-84-0);
sertindole
179
CA 02726300 2010-12-22
(CAS RN 106516-24-9); eplivanserin (CAS RN 130579-75-8) or eplivanserin
fumarate (CAS
RN 130580-02-8); lubazodone hydrochloride (CAS RN 161178-10-5); cyproheptadine
(CAS
RN 129-03-3); pizotyline or pizotifen (CAS RN 15574-96-6); mesulergine (CAS RN
64795-
35-3); irindalone (CAS RN 96478-43-2); MDL 11939 (CAS RN 107703-78-6); or
pruvanserin (CAS RN 443144-26-1).
103691 Additional non-limiting examples of modulators include reported 5-HT2C
agonists
or partial agonists, such as m-chlorophenylpiperazine; or 5-HT2A receptor
inverse agonists,
such as ACP 103 (CAS RN: 868855-07-6), APD125 (from Arena Pharmaceuticals),
AVE
8488 (from Sanofi-Aventis) or TGWOOAD/AA(from Fabre Kramer Pharmaceuticals).
[03701 Additionally, a 5HTR agent may be a reported 5HT3 receptor antagonist
such as
azasetron (CAS RN 123039-99-6); ondansetron (CAS RN 99614-02-5) or ondansetron
hydrochloride (CAS RN 99614-01-4); cilansetron (CAS RN 120635-74-7); aloxi or
palonosetron hydrochloride (CAS RN 135729-62-3); palenosetron (CAS RN 135729-
61-2 or
135729-56-5); cisplatin (CAS RN 15663-27-1); lotronex or alosetron
hydrochloride (CAS
RN 122852-69-1); anzemet or dolasetron mesylate (CAS RN 115956-13-3);
zacopride or R-
zacopride; E-3620 ([3(S)-endo]-4-amino-5-chloro-N-(8-methyl- 8-
azabicyclo[3.2.1-]oct-3-yl-
2[(1-methyl-2-butynyl)oxy]benzamide) or E-3620 HCl (3(S)-endo-4-amino-5-chloro-
N-(8-
methyl- 8- azabicyclo [3.2.1] oct- 3-yl)-2-(1-methyl-2-butinyl)oxy)-benzamide-
HC1); YM
060 or ramosetron hydrochloride (CAS RN 132907-72-3); a thieno[2,3-
d]pyrimidine
derivative antagonist described in U.S. Patent 6,846,823, such as DDP 225 or
MCI 225 (CAS
RN 135991-48-9); marinol or dronabinol (CAS RN 1972-08-3); or lac hydrin or
ammonium
lactate (CAS RN 515-98-0); kytril or granisetron hydrochloride (CAS RN 107007-
99-8);
bemesetron (CAS RN 40796-97-2); tropisetron (CAS RN 89565-68-4); zatosetron
(CAS RN
123482-22-4); mirisetron (CAS RN 135905-89-4) or mirisetron maleate (CAS RN
148611-
75-0); or renzapride (CAS RN 112727-80-7).
[03711 It is a specific object of the invention to provide the compounds shown
below
which are 5HT3 antagonists.
180
CA 02726300 2010-12-22
N
N
NJ
O O NH
NH O
\N N
CI N :LO
Compound A Compound B Compound C
[0372] It is another specific object of the invention to use the compounds
shown supra and
analogs of Compound A, Compound B and Compound C.
[0373] It is another specific object of the invention to provide 5HT3
antagonists which can
be represented by the following formulae which are.
[0374] In a first aspect, a compound of structural Formula (XII) is provided:
X
\Ar1_A_B_R38
R37
XII
or a salt, hydrate, solvate or N-oxide thereof wherein:
ArI a five or six membered aryl, heteroaryl or cycloalkyl ring;
A is SO2; C=O; C=S; or C=NR39
B is NH, NR40, 0, S alkyl, substituted alkyl,
R38 is selected from the group consisting of hydrogen, alkyl, substituted
alkyl, aryl,
substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl,
heteroalkyl, substituted
heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted
heteroarylalkyl,
OR42, S(O)bR42, NR42R43, CONR42R43, C02R42, NR42CO2R43, NR42CONR43R44,
NR42CSNR43R44, NR42C(=NH)NR43R44, S02NR41R42, NR4'S02R42, NR41S02NR42R43,
P(O)(OR41)(OR42), and P(O)(R41)(OR42);
b=0, 1,or2
R39 is selected from the group consisting of hydrogen, alkyl, and substituted
alkyl.
X is selected from the group consisting of hydrogen, halogen, alkyl,
substituted alkyl,
aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted
acyl, heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,
substituted
heteroarylalkyl, CN, NO2, OR42, S(O)bR42, NR42R43, CONR42R43, C02R42,
NR42CO2R43,
181
CA 02726300 2010-12-22
NR42CONR43R44, NR42CSNR43R44, NR42C(=NH)NR43R44, SO2NR41R42, NR41SO2R42,
NR4'SO2NR42R43, P(O)(OR41)(OR42), and P(O)(R41)(OR42);
R37 is selected from the group consisting of hydrogen, halogen, alkyl,
substituted
alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl,
substituted acyl, heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,
substituted
heteroarylalkyl, CN, NO2, OR42, S(O)bR42, NR42R43, CONR42R43, CO2R42,
NR42CO2R43,
NR42CONR43R44, NR42CSNR43R44, NR42C(=NH)NR43R44, SO2NR41R42, NR41SO2R42,
NR41SO2NR42R43, P(O)(OR41)(OR42), and P(O)(R41)(OR42);
R40-R44 are independently selected from the group consisting of hydrogen,
alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,
heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl
and substituted
heteroarylalkyl or alternatively, R4' and R42, R42 and R43, R43 and R44,
together with the
atoms to which they are bonded form a cycloheteroalkyl or substituted
cycloheteroalkyl ring;
or alternatively, X and/or at least one R37 together with the atoms to which
they are
bonded form an aryl, substituted aryl, heteroaryl, substituted heteroaryl,
cycloalkyl,
substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring
where the ring is
optionally fused to another aryl, substituted aryl, heteroaryl, substituted
heteroaryl,
cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted
cycloheteroalkyl ring;
or alternatively, X and/or at least one R 38 , R41, R42, R43 or R44 together
with the atoms
to which they are bonded form an aryl, substituted aryl, heteroaryl,
substituted heteroaryl,
cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted
cycloheteroalkyl ring
where the ring is optionally fused to another aryl, substituted aryl,
heteroaryl, substituted
heteroaryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or
substituted
cycloheteroalkyl ring;
103751 In a second aspect the invention provides compounds of structural
Formula (XIX)
shown below:
R70
g1'
X5 A1.
R69 ~\ \ Z1-R77
Y1
R78
XIX
or a salt, hydrate, solvate or N-oxide thereof wherein:
182
CA 02726300 2010-12-22
Al is SO2; C=O; C=S; or C=N R71
B' is NH, N R72, 0, S alkyl, substituted alkyl,
R69 is selected from the group consisting of hydrogen, halogen, alkyl,
substituted
alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl,
substituted acyl, heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,
substituted
heteroarylalkyl, CN, NO2, 0 R74, S(O)ff R74, NR 74 R75, CON R74 R75, CO2 R74,
NR 74CO2
R75, N R74CON R75 R76, NR 74CSN R75 R76, NR 14 C(=NH)N R75 R76, SO2N R73 R74,
N
R73SO2 R74, N R73SO2N R74 R75, P(O)(O R73)(O R74), and P(O)( R73)(O R74);
X5 is selected from the group consisting of hydrogen, halogen, alkyl,
substituted alkyl,
aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted
acyl, heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,
substituted
heteroarylalkyl, CN, NO2, 0 R74, S(O)f, R74, N R74 R75, CON R74 R75, CO2 R74,
N R74C02
R75, N R74CON R75 R76, NR 74CSN R75 R76, NR 74 C(=NH)N R75 R76, SO2N R73 R74,
N
R73SO2 R74, NR 71 S02N R74 R75, P(O)(O R73)(O R74), and P(O)( R73)(O R74);
R70 is selected from the group consisting of hydrogen, alkyl, substituted
alkyl, aryl,
substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl,
heteroalkyl, substituted
heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted
heteroarylalkyl, 0
R74, S(O), R74, N R74 R75, CON R74 R75, CO2 R74, NR 74 C02 R75, NR 74 CON R75
R76, N
R74CSN R75 R76, N R74C(=NH)N R75 R76,, SO2N R73 R74, NR 71 S02 R74, NR 71 S02N
R74 R75,
P(O)(O R73)(O R74), and P(O)( R73)(O R74);
ff = 0, 1, or 2
R71 is selected from the group consisting of hydrogen, alkyl, and substituted
alkyl.
Y1 and Z1 are independently selected from N and C
R78 is selected from the group consisting of hydrogen, CI-C6 alkyl, and Ci-C6
substituted alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C6 alkyl, C1-C6
alkenyl, C,-C6
substituted alkenyl, C,-C6 alkynyl, C,-C6 substituted alkynyl, aryl,
arylalkyl, heteroaryl,
heteroarylalkyl
Or alternatively, R69 and R78 together with the atoms to which they are bonded
form
an aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl,
cycloheteroalkyl or substituted cycloheteroalkyl ring where the ring is
optionally fused to
another aryl, substituted aryl, heteroaryl, substituted heteroaryl,
cycloalkyl, substituted
cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring;
R77 is selected from the group consisting of hydrogen, C,-C6 alkyl, and C,-C6
substituted alkyl,
183
CA 02726300 2010-12-22
or alternatively, R77 and B' together with the atoms to which they are bonded
form an
aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl,
cycloheteroalkyl or substituted cycloheteroalkyl ring where the ring is
optionally fused to
another aryl, substituted aryl, heteroaryl, substituted heteroaryl,
cycloalkyl, substituted
cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring;
[03761 A preferred embodiment of the invention provides compounds having
structural
Formula (XX) shown below:
R70
0 B1"
/
Z
Y
%
R78
XX
or a salt, hydrate, solvate or N-oxide thereof wherein:
Y' and Z1 are independently selected from N and C
R78 is selected from the group consisting of hydrogen, C,-C6 alkyl, and C1-C6
substituted alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C6 alkyl, C1-C6
alkenyl, C1-C6
substituted alkenyl, C1-C6 alkynyl, C1-C6 substituted alkynyl, aryl,
arylalkyl, heteroaryl,
heteroarylalkyl
B' is NH, N R72, or 0
R70 is selected from the group consisting of hydrogen, alkyl, substituted
alkyl, aryl,
substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl,
heteroalkyl, substituted
heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted
heteroarylalkyl, 0
R74, S(O)ff R74, NR 74 R75, CON R74 R7s, CO2 R74, NR 74 C02 R75, NR 74 CON R7s
R76, N
R74CSN R75 R76, N R74C(=NH)N R7s R76, SO2N R73 R74, NR 13 S02 R74, NR 71 S02N
R74 R75,
P(O)(O R73)(O R74), and P(O)( R73)(OR14);
103771 Some preferred embodiments provide compounds as described above
wherein, R70,
forms a ring that can be fused with additional substituted or unsubstituted
rings. Non-
limiting examples of such a ring includes groups having the formula (y), (z),
and (aa) below:
((y)
184
CA 02726300 2010-12-22
(CH2)hh
(z)
R79
N~
1-Zn
(aa)
Wherein, gg, hh and ii are independently selected from 1, 2 or 3.
R79 is selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6
substituted alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C6 alkyl, or a group
(CH2))R80
Where jj is 1,2 or 3 and R80 is thienyl, pyrrolyl, furyl or imidazolyl
optionally substituted by
one or 2 substituents selected from Halogen, C1-C6 alkyl, C1-C6 alkoxy,
Substituted C1-C6
alkyl, aryl or substituted aryl.
[03781 Some even more preferred embodiments provide compounds as described
above
wherein, R70 forms a ring that can be fused with additional substituted or
unsubstituted rings
and can comprise at least one double bond. Preferred embodiments of such a
ring includes
groups having the formulas:
N O N
N
And their stereoisomers
[03791 A more preferred embodiment of the invention provides compounds having
structural Formula (XXI) shown below:
R81
O B1"
N
0
XXI
B' is NH, NR82, or 0
185
CA 02726300 2010-12-22
R78 is selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6
substituted alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C6 alkyl, C1-C6
alkenyl, C1-C6
substituted alkenyl, C1-C6 alkynyl, C1-C6 substituted alkynyl, aryl,
arylalkyl, heteroaryl,
heteroarylalkyl
each R81 is independently selected from the group consisting of hydrogen,
alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,
acyl, substituted acyl,
heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl,
heteroarylalkyl, and
substituted heteroarylalkyl.
R82is selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6
substituted alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C6 alkyl,
[03801 Some preferred embodiments provide compounds as described above
wherein, R81,
forms a ring that can be fused with additional substituted or unsubstituted
rings. Non-
limiting examples of such a ring includes groups having the formula (y), (z),
and (aa) below:
(CH2)99 N-R79
(y)
(CH2)nn
(z)
R79
N~
CH2)11
(aa)
Wherein, gg, hh and ii are independently selected from 1, 2 or 3.
R79 is selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6
substituted alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C6 alkyl, or a group
(CH2)jj Rso
Where jj is 1,2 or 3 and R80 is thienyl, pyrrolyl, furyl or imidazolyl
optionally substituted by
one or 2 substituents selected from Halogen, C1-C6 alkyl, C1-C6 alkoxy,
Substituted C1-C6
alkyl, aryl or substituted aryl.
186
CA 02726300 2010-12-22
103811 Some even more preferred embodiments provide compounds as described
above
wherein, R81 forms a ring that can be fused with additional substituted or
unsubstituted rings
and can comprise at least one double bond. Preferred embodiments of such a
ring system
includes groups having the formulas:
N O N
~,.N
And their stereoisomers
103821 An especially preferred aspect the invention provides a compound having
the
structure below:
N
O
NH
,N
CCIN
Or a salt, hydrate, solvate or N-oxide thereof
103831 Another preferred embodiment of the invention provides compounds having
structural Formula (XXII) shown below:
R81
O B" N
R78
XXII
B' is NH, N R82, or O
R78 is selected from the group consisting of hydrogen, CI-C6 alkyl, and CI-C6
substituted alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C,-C6 alkyl, C1-C6
alkenyl, C1-C6
substituted alkenyl, C1-C6 alkynyl, C1-C6 substituted alkynyl, aryl,
arylalkyl, heteroaryl,
heteroarylalkyl
187
CA 02726300 2010-12-22
each R81 is independently selected from the group consisting of hydrogen,
alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,
acyl, substituted acyl,
heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl,
heteroarylalkyl, and
substituted heteroarylalkyl.
R82 is selected from the group consisting of hydrogen, C I -C6 alkyl, and C 1-
C6
substituted alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-CI-C6 alkyl,
[03841 Some preferred embodiments provide compounds as described above
wherein, R81,
forms a ring that can be fused with additional substituted or unsubstituted
rings. Non-
limiting examples of such a ring includes groups having the formula (y), (z),
and (aa) below:
(CH2)99 N-R79
(Y)
(CH2)nn
(z)
R79
N~
((aa)
Wherein, gg, hh and ii are independently selected from 1, 2 or 3.
R79 is selected from the group consisting of hydrogen, CI-C6 alkyl, and CI-C6
substituted alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-CI-C6 alkyl, or a group
(CH2))j R
Where jj is 1,2 or 3 and R80 is thienyl, pyrrolyl, furyl or imidazolyl
optionally substituted by
one or 2 substituents selected from Halogen, C1-C6 alkyl, CI-C6 alkoxy,
Substituted CI-C6
alkyl, aryl or substituted aryl.
103851 Some even more preferred embodiments provide compounds as described
above
wherein, R81 forms a ring that can be fused with additional substituted or
unsubstituted rings
and can comprise at least one double bond. Preferred embodiments of such a
ring system
includes groups having the formulas:
188
CA 02726300 2010-12-22
N
N O
N
And their stereoisomers
103861 Another especially preferred aspect the invention provides compounds
having the
structure below:
O
N
~.N
O O
NH NH
H I N
H
Or a salt, hydrate, solvate or N-oxide thereof
103871 Another preferred embodiment of the invention provides compounds having
structural Formula (XXIII) shown below:
0 B" R81
R83 R77
Y
R78
XXIII
Or a salt, hydrate, solvate or N-oxide thereof wherein:
Y' is independently selected from N and C
R78 is selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6
substituted alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C6 alkyl, C1-C6
alkenyl, C1-C6
substituted alkenyl, C1-C6 alkynyl, C1-C6 substituted alkynyl, aryl,
arylalkyl, heteroaryl,
heteroarylalkyl
R83, is selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6
substituted alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C6 alkyl, C3-C6
cycloalkyl-C1-C6
189
CA 02726300 2010-12-22
substituted alkyl, C1-C6 alkenyl, C1-C6 substituted alkenyl, C1-C6 alkynyl, C,-
C6 substituted
alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl
R77 is selected from the group consisting of hydrogen, C,-C6 alkyl, and C,-C6
substituted alkyl,
or alternatively, R78 and R83 together with the atoms to which they are bonded
form an
aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl,
cycloheteroalkyl or substituted cycloheteroalkyl ring.
B1 is NH, N R72, or CR84R85
Wherein R84 and R85 are independently selected from the group consisting of
hydrogen, C,-C6 alkyl, and C1-C6 substituted alkyl, C3-C6 cycloalkyl, C3-C6
cycloalkyl-C1-
C6 alkyl.
Alternatively, R77 and B1 together with the atoms to which they are bonded
form an
aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl,
cycloheteroalkyl or substituted cycloheteroalkyl ring.
And R81 is selected from the group consisting of hydrogen, alkyl, substituted
alkyl,
aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted
acyl, heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,
and substituted
heteroarylalkyl.
[03881 A preferred embodiment of the invention provides compounds having
structural
Formula (XXIII) as described above where R78 is selected from the group
consisting of
hydrogen, C1-C6 alkyl, and C1-C6 substituted alkyl, C3-C6 cycloalkyl, C1-C6
alkenyl, aryl,
and arylalkyl, and R81 is a substituted alky group as shown in the formula
below:
Ar5
Where Ar5 is a substituted or unsubstituted five or six membered aryl, or
heteroaryl
ring.
[03891 Another more preferred embodiment of the invention provides compounds
having
structural Formula (XXIII) as described above where R78 is selected from the
group
consisting of hydrogen, C1-C6 alkyl, and C,-C6 substituted alkyl, C3-C6
cycloalkyl, C1-C6
alkenyl, aryl, and arylalkyl, and R81 is a substituted alky group as shown in
the formula
below:
190
CA 02726300 2010-12-22
R86
,=N
NRs7
R88
Where one of the groups R86, R87 and R88 are selected from the group
consisting of
hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, phenyl, phenyl C1-C3
alkyl and each
of the remaining 2 groups may be the same or different and are selected from
hydrogen, and
C1-C6 alkyl.
[03901 Another even more preferred embodiment of the invention provides
compounds
having structural Formula (XXIII) as described above where R78 is selected
from the group
consisting of hydrogen, C1-C6 alkyl, and C1-C6 substituted alkyl, C3-C6
cycloalkyl, C1-C6
alkenyl, aryl, and arylalkyl, and R81 is a substituted alky group as shown in
the formula
below:
R86
N R87
R89
Where one of the groups R86 and R87 are independently selected from the group
consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, phenyl,
phenyl C1-C3
alkyl and the remaining group may be the same or different and are selected
from hydrogen,
and C1-C6 alkyl.
R89 is selected from hydrogen, C1-C6 alkyl, or C1-C6 substituted alkyl
103911 Another even more preferred embodiment of the invention provides
compounds
having structural Formula (XXIV) shown below or a salt, hydrate, solvate or N-
oxide thereof
wherein:
O R81
N
R78
XXIV
R78 is selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6
substituted alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C6 alkyl, C1-C6
alkenyl, C1-C6
191
CA 02726300 2010-12-22
substituted alkenyl, C1-C6 alkynyl, C1-C6 substituted alkynyl, aryl,
arylalkyl, heteroaryl,
heteroarylalkyl
And R81 is selected from the group consisting of hydrogen, alkyl, substituted
alkyl,
aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted
acyl, heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,
and substituted
heteroarylalkyl.
103921 An even more preferred embodiment of the invention provides compounds
having
structural Formula (XXIV) as described above where R78 is selected from the
group
consisting of hydrogen, C1-C6 alkyl, and C1-C6 substituted alkyl and R81 is a
substituted alky
group as shown in the formula below:
/-Ar5
Where Ar5 is a substituted or unsubstituted five or six membered aryl, or
heteroaryl
ring.
[03931 Another even more preferred embodiment of the invention provides
compounds
having structural Formula (XVIII) as described above where R78 is selected
from the group
consisting of hydrogen, C1-C6 alkyl, and C1-C6 substituted alkyl and R81 is a
substituted alky
group as shown in the formula below:
R86
~-N
~N 8 R87 R Where one of the groups R86, R87 and R88 are selected from the
group consisting of
hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, phenyl, phenyl C1-C3
alkyl and each
of the remaining 2 groups may be the same or different and are selected from
hydrogen, and
C1-C6 alkyl.
[03941 Another especially preferred embodiment of the invention provides
compounds
having structural Formula (XVIII) as described above where R78 is selected
from the group
192
CA 02726300 2010-12-22
consisting of hydrogen, C1-C6 alkyl and R81 is a substituted alky group as
shown in the
formula below:
R86
N
N 1R87
K89
Where one of the groups R86 and R87 are independently selected from the group
consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, phenyl,
phenyl C1-C3
alkyl and the remaining group may be the same or different and are selected
from hydrogen,
and C 1-C6 alkyl.
R89 is selected from hydrogen, C1-C6 alkyl, or C1-C6 substituted alkyl.
103951 In yet another especially preferred embodiment of the invention
provides a
compound having the structure below:
N
O N
H
N
Or a salt, hydrate, solvate or N-oxide thereof
103961 Yet another preferred embodiment of the invention provides compounds
having
structural Formula (XXV) shown below wherein:
193
CA 02726300 2010-12-22
R81
O
N
R78
XXV
or a salt, hydrate, solvate or N-oxide thereof wherein:
R78 is selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6
substituted alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C6 alkyl, CI-C6
alkenyl, C1-C6
substituted,alkenyl, C1-C6 alkynyl, C1-C6 substituted alkynyl, aryl,
arylalkyl, heteroaryl,
heteroarylalkyl
kk is 0, 1 or 2 and,
R81 is selected from the group consisting of hydrogen, alkyl, substituted
alkyl, aryl,
substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl,
heteroalkyl, substituted
heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and
substituted
heteroarylalkyl.
(03971 A more preferred embodiment of the invention provides compounds having
structural Formula (XXV) as described above where R78 is selected from the
group
consisting of hydrogen, C1-C6 alkyl, and C1-C6 substituted alkyl and R81 is a
substituted alky
group as shown in the formula below:
rAr5
Where Ar5 is a substituted or unsubstituted five or six membered aryl, or
heteroaryl
ring.
103981 Another even more preferred embodiment of the invention provides
compounds
having structural Formula (XXV) as described above where R78 is selected from
the group
consisting of hydrogen, C1-C6 alkyl, and C1-C6 substituted alkyl and R81 is a
substituted alky
group as shown in the formula below:
194
CA 02726300 2010-12-22
R86
~-N
N R87
R88
Where one of the groups R86, R87 and R88 are selected from the group
consisting of
hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, phenyl, phenyl C1-C3
alkyl and each
of the remaining 2 groups may be the same or different and are selected from
hydrogen, and
C 1-C6 alkyl.
[0399] Another even more preferred embodiment of the invention provides
compounds
having structural Formula (XXV) as described above where R78 is selected from
the group
consisting of hydrogen, C1-C6 alkyl and R81 is a substituted alky group as
shown in the
formula below:
R86
N R87
R89
Where one of the groups R86 and R87 are independently selected from the group
consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, phenyl,
phenyl C1-C3
alkyl and the remaining group may be the same or different and are selected
from hydrogen,
and C1-C6 alkyl.
R89 is selected from hydrogen, C1-C6 alkyl, or C1-C6 substituted alkyl.
[0400] Yet another especially preferred embodiment of the invention provides
compounds
having structural Formula (XXVI) shown below or a salt, hydrate, solvate or N-
oxide thereof
wherein:
R86
~ N
N c$R87
N
R78
XXVI
195
CA 02726300 2010-12-22
R78 is selected from the group consisting of hydrogen, C1-C6 alkyl
Where one of the groups R86, R87 and R88 are selected from the group
consisting of
hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, phenyl, phenyl C1-C3
alkyl and each
of the remaining 2 groups may be the same or different and are selected from
hydrogen, and
C 1-C6 alkyl.
104011 In yet another especially preferred aspect the invention provides a
compound
having the structure below:
~-- N
O NJ
N
Or a salt, hydrate, solvate or N-oxide thereof
10402] Yet another preferred embodiment of the invention provides compounds
having
structural Formula (XXVII) shown below or a salt, hydrate, solvate or N-oxide
thereof
wherein:
Rah
\/=N
N Raj
O Raa
N
it
XXVII
kk and 11 are independently selected from 0,1 or 2 and
Where one of the groups R86, R87 and R88 are selected from the group
consisting of
hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, phenyl, phenyl C1-C3
alkyl and each
of the remaining 2 groups may be the same or different and are selected from
hydrogen, and
C 1-C6 alkyl.
196
CA 02726300 2010-12-22
104031 Another even more preferred embodiment of the invention provides
compounds
having structural Formula (XXVII) as described above where kk and 11 are both
equal to one
and where one of the groups R86, R87 and R88 are selected from the group
consisting of
hydrogen, C,-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, phenyl, phenyl C1-C3
alkyl and each
of the remaining 2 groups may be the same or different and are selected from
hydrogen, and
C1-C6 alkyl
104041 In yet another especially preferred embodiment of the invention
provides a
compound having the structure below:
--N
0 NJ
N
or a salt, hydrate, solvate or N-oxide thereof
104051 In yet another embodiment of the invention provides compounds having
the
structure formula (XXVIII) below or a salt, hydrate, solvate or N-oxide
thereof wherein:
X6
\Ara-A1_B1_R71
R5
mn
XXVIII
Ar4 a five or six membered aryl, heteroaryl or cycloalkyl ring;
A' is SO2; C=O; or C=N R7'
B' is NH, N R72, 0, S, Alkyl, substituted alkyl
mn is 0, 1, 2, 3, or 4
R70 is selected from the group consisting of hydrogen, alkyl, substituted
alkyl, aryl,
substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl,
heteroalkyl, substituted
heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted
heteroarylalkyl, 0
R74, S(O)rf R74, N R74 R7s, CON R74 R7s, CO2 R74, NR 74CO, R7S, N R74CON R7s
R76, N
,
R74CSN R7s R76, N R74C(=NH)N R7s R76, SO2NR73 R74, NR73S0274, N R73SO2NR74 R71
P(O)(O R73)(OR74), and P(O)( R73)(OR74);
197
CA 02726300 2010-12-22
ff=0, 1,or2
R71 is selected from the group consisting of hydrogen, alkyl, and substituted
alkyl.
X6 is selected from the group consisting of hydrogen, halogen, perfluoroalkyl,
perfluoroalkoxy, alkyl, alkenyl, alkynyl, hydroxy, oxo, mercapto, alkylthio,
alkoxy, aryl or
heteroaryl, aryloxy or heteroaryloxy, arylalkyl or heteroarylalkyl, arylalkoxy
or
heteroarylalkoxy, amino, alkyl- and dialkylamino groups, carbamoyl,
alkylcarbonyl,
carboxyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylamino carbonyl,
arylcarbonyl,
aryloxycarbonyl, alkylsulfonyl, arylsulfonyl, cycloalkyl, cyano, CI-C6
alkylthio, arylthio,
nitro, keto, acyl, phosphate or phosphonyl, sulfamyl, sulfonyl, sulfinyl, and
combinations
thereof
Each R58 is independently is selected from the group consisting of hydrogen,
halogen,
perfluoroalkyl, perfluoroalkoxy, alkyl, alkenyl, alkynyl, hydroxy, oxo,
mercapto, alkylthio,
alkoxy, aryl or heteroaryl, aryloxy or heteroaryloxy, arylalkyl or
heteroarylalkyl, arylalkoxy
or heteroarylalkoxy, amino, alkyl- and dialkylamino groups, carbamoyl,
alkylcarbonyl,
carboxyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylamino carbonyl,
arylcarbonyl,
aryloxycarbonyl, alkylsulfonyl, arylsulfonyl, cycloalkyl, cyano, CI-C6
alkylthio, arylthio,
nitro, keto, acyl, phosphate or phosphonyl, sulfamyl, sulfonyl, sulfinyl, and
combinations
thereof.
R72- R76 are independently selected from the group consisting of hydrogen,
alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,
heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl
and substituted
heteroarylalkyl or alternatively, R73 and R74, R74 and R75, R75 and R76,
together with the
atoms to which they are bonded form a cycloheteroalkyl or substituted
cycloheteroalkyl ring;
or alternatively, X6 and/or at least one R58 together with the atoms to which
they are
bonded form an aryl, substituted aryl, heteroaryl, substituted heteroaryl,
cycloalkyl,
substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring
where the ring is
optionally fused to another aryl, substituted aryl, heteroaryl, substituted
heteroaryl,
cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted
cycloheteroalkyl ring;
or alternatively, X6 and/or at least one R70, R72 , R73, R74, R75 or R76
together with the
atoms to which they are bonded form an aryl, substituted aryl, heteroaryl,
substituted
heteroaryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or
substituted
cycloheteroalkyl ring where the ring is optionally fused to another aryl,
substituted aryl,
198
CA 02726300 2010-12-22
heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl,
cycloheteroalkyl or
substituted cycloheteroalkyl ring;
[04061 In yet another preferred embodiment of the invention provides compounds
having
the structure formula (XXIX) below :
O B1 R70
R94 R91
Rss/.~\ R92
XXIX
Where B' is NH or 0 and R91, R92, R93 and R94 are independently selected from
hydrogen, halogen alkyl, alkoxy, amino, acylamino, hydroxyl or nitro and R70
forms a ring
that can be fused with additional substituted or unsubstituted rings. Non-
limiting examples of
such a ring includes groups having the formula bb, cc, and dd below:
H CHz 00 (CH2)g N-R7s
(bb)
H2)oo
(cc)
R79
N~
HcH200 ~CHz)ii
(dd)
Wherein gg, hh, ii and oo are independently selected from 0, 1, 2 or 3.
R79 is selected from the group consisting of hydrogen, C1-C6 alkyl, and C,-C6
substituted alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C6 alkyl, or a group
(CH2)jj Rso
Where jj is 1,2 or 3 and R80 is thienyl, pyrrolyl, furyl or imidazolyl
optionally substituted by
one or 2 substituents selected from Halogen, C1-C6 alkyl, C1-C6 alkoxy,
Substituted C1-C6
alkyl, aryl or substituted aryl.
[04071 In yet another more preferred embodiment of the invention provides
compounds
having the structure formula (XXX) below or a salt, hydrate, solvate or
thereof wherein:
199
CA 02726300 2010-12-22
H
O N, R70
O. R95
R91
R92
xxx
R91 is hydrogen, chloro or bromo, R92 is hydrogen or amino, R95 is selected
from C1-
C6 alkyl, C1-C6 substituted alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C6
alkyl and R70
forms a ring that can be fused with additional substituted or unsubstituted
rings. Non-
limiting examples of such a ring includes groups having the formula bb, cc,
and dd below:
H CH2 00 (CH2)g N-R79
(bb)
N
I
HCH2)OO
(cc)
R79
N~
HcH200
(dd)
Wherein gg, hh, ii and oo are independently selected from 0,1, 2 or 3.
R79 is selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6
substituted alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C6 alkyl, or a group
(CH2)j R80
Where jj is 1,2 or 3 and R80 is thienyl, pyrrolyl, furyl or imidazolyl
optionally substituted by
one or 2 substituents selected from Halogen, C1-C6 alkyl, C1-C6 alkoxy,
Substituted C1-C6
alkyl, aryl or substituted aryl.
[04081 An especially more preferred embodiment of the invention provides
compounds
having the structure formula (XXX) above or a salt, hydrate, solvate or
thereof wherein R91 is
hydrogen, chloro or bromo, R92 is hydrogen or amino, R95 is selected from
methyl or 1-
(methylsulfinyl)ethyl and R70 is either of the formula e above where oo is 0
and hh is 2, C1-C6
alkyl, and C1-C6 substituted alkyl,
200
CA 02726300 2010-12-22
[04091 In yet another especially preferred embodiment of the invention
provides
compounds having the structure:
0
NN
H N H
CI \ O~ CI \ O
H2N H2N ,g-
O
Or a salt, hydrate, solvate or N-oxide thereof.
[04101 In yet another more preferred embodiment of the invention provides
compounds
having the structure formula (XXXI) below or a salt, hydrate, solvate or
thereof wherein:
H
0 N_R7o
O
R91 N O
R92 R96
XXXI
R91 is hydrogen, chloro or bromo, R92 is hydrogen or amino, R96 is selected
from
hydrogen, C1-C6 alkyl, and C1-C6 substituted alkyl, C3-C6 cycloalkyl, C3-C6
cycloalkyl-C1-
C6 alkyl and R70 forms a ring that can be fused with additional substituted or
unsubstituted
rings. Non-limiting examples of such a ring includes groups having the formula
bb, cc, and
dd below:
-(CH2 00 (CH2)9 N-R79
(bb)
N
I
Hc2)oo
(cc)
R79
N~
HCH2 0~__1CH2)~~
(dd)
201
CA 02726300 2010-12-22
Wherein gg, hh, ii and oo are independently selected from 0,1, 2 or 3.
R79 is selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6
so
substituted alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C6 alkyl, or a group
(CH2)õ R
Where jj is 1,2 or 3 and R80 is thienyl, pyrrolyl, furyl or imidazolyl
optionally substituted by
one or 2 substituents selected from Halogen, C1-C6 alkyl, C1-C6 alkoxy,
Substituted C1-C6
alkyl, aryl or substituted aryl.
[0411] In yet another especially preferred embodiment of the invention
provides a
compound having the structure:
N
O NH
O
CI N1O
I
Or a salt, hydrate, solvate or N-oxide thereof.
[0412] In yet another especially preferred embodiment of the invention
provides
compounds having the structure formula (XXXII) below or a salt, hydrate,
solvate or thereof
wherein:
O R70
N O
R91 ~ ~
R92
XXXII
R91 is hydrogen, chloro or bromo, R92 is hydrogen or amino, and R70 forms a
ring that can be
fused with additional substituted or unsubstituted rings. Non-limiting
examples of such a
ring includes groups having the formula bb, cc, and dd below:
H CH2 00 (CH2)9 N-R79
(bb)
202
CA 02726300 2010-12-22
N
I
HCH2 CH2h
00
(cc)
R79
HCH2 O~CH2)"
(dd)
Wherein gg, hh, ii and oo are independently selected from 0,1, 2 or 3.
R79 is selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6
ao
substituted alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C6 alkyl, or a group
(CH2)~ R
Where jj is 1, 2 or 3 and R80 is thienyl, pyrrolyl, furyl or imidazolyl
optionally substituted by
one or 2 substituents selected from Halogen, C1-C6 alkyl, C1-C6 alkoxy,
Substituted C1-C6
alkyl, aryl or substituted aryl.
[04131 In yet another especially preferred embodiment of the invention
provides a
compound having the structure:
N
O
N
O
CI
H2N
Or a salt, hydrate, solvate or N-oxide thereof.
104141 In yet another more preferred embodiment of the invention provides
compounds
having the structure formula (XXXIII) below or a salt, hydrate, solvate or
thereof wherein:
O R70
N
R91
R92
XXXIII
203
CA 02726300 2010-12-22
R9' is hydrogen, chloro or bromo, R92 is hydrogen or amino, and R70 forms a
ring that
can be fused with additional substituted or unsubstituted rings. Non-limiting
examples of
such a ring includes groups having the formula bb, cc, and dd below:
H CH2 00 (CH2)9 N-R79
(bb)
N
Hc-2)0o
(cc)
R79
HCH2 o
(dd)
Wherein gg, hh, ii and oo are independently selected from 0, 1, 2 or 3.
R79 is selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6
substituted alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C6 alkyl, or a group
(CH2)1J R80
Where jj is 1,2 or 3 and R80 is thienyl, pyrrolyl, furyl or imidazolyl
optionally substituted by
one or 2 substituents selected from Halogen, C1-C6 alkyl, C1-C6 alkoxy,
Substituted C1-C6
alkyl, aryl or substituted aryl.
104151 In yet another especially preferred embodiment of the invention
provides a
compound having the structure:
N
O
N
or a salt, hydrate, solvate or N-oxide thereof
[04161 Alternatively, a 5HTR agent may be a reported 5HT4 receptor agonist (or
partial
agonist). In some embodiments, a reported 5HT4 receptor agonist or partial
agonist is a
substituted benzamide, such as cisapride; individual, or a combination of,
cisapride
enantiomers ((+) cisapride and (-) cisapride); mosapride; and renzapride as
non-limiting
204
CA 02726300 2010-12-22
examples. In other embodiments, the chemical entity is a benzofuran
derivative, such as
prucalopride. Additional embodiments include indoles, such as tegaserod, or
benzimidazolones. Other non-limiting chemical entities reported as a 5HT4
receptor agonist
or partial agonist include zacopride (CAS RN 90182-92-6), SC-53116 (CAS RN
141196-99-
8) and its racemate SC-49518 (CAS RN 146388-57-0), BIMUI (CAS RN 127595-43-1),
TS-
951 (CAS RN 174486-39-6), or ML10302 CAS RN 148868-55-7). Additional non-
limiting
chemical entities include metoclopramide, 5-methoxytryptamine, RS67506, 2-[1-
(4-
piperonyl)piperazinyl]benzothiazole, RS6633 1, BIMU8, SB 205149 (the n-butyl
quaternary
analog of renzapride), or an indole carbazimidamide as described by Buchheit
et al. ("The
serotonin 5-HT4 receptor. 2. Structure-activity studies of the indole
carbazimidamide class of
agonists." J Med Chem. (1995) 38(13):2331-8). Yet additional non-limiting
examples
include norcisapride (CAS RN 102671-04-5) which is the metabolite of
cisapride; mosapride
citrate; the maleate form of tegaserod (CAS RN 189188-57-6); zacopride
hydrochloride
(CAS RN 99617-34-2); mezacopride (CAS RN 89613-77-4); SK-951 ((+-)-4-amino-N-
(2-(I-
azabicyclo(3.3.0)octan-5-yl)ethyl)-5-chloro-2,3 -dihydro-2-methylbenzo(b)furan-
7-
carboxamide hemifumarate); ATI-7505, a cisapride analog from ARYx
Therapeutics; SDZ-
216-454, a selective 5HT4 receptor agonist that stimulates cAMP formation in a
concentration dependent manner (see Markstein et al. "Pharmacological
characterisation of 5-
HT receptors positively coupled to adenylyl cyclase in the rat hippocampus."
Naunyn
Schmiedebergs Arch Pharmacol. (1999) 359(6):454-9); SC-54750, or
aminomethylazaadamantane; Y-36912, or 4-amino-N-[I-[3-
(benzylsulfonyl)propyl]piperidin-
4-ylmethyl]-5-chloro-2-methoxybenzamide as disclosed by Sonda et al.
("Synthesis and
pharmacological properties of benzamide derivatives as selective serotonin 4
receptor
agonists." Bioorg Med Chem. (2004) 12(10):2737-47); TKS159, or 4-amino-5-
chloro-2-
methoxy-N-[(2S,4S)- 1-ethyl-2- hydroxymethyl-4-pyrrolidinyl] benzamide, as
reported by
Haga et al. ("Effect of TKS 159, a novel 5-hydroxytryptamine4 agonist, on
gastric contractile
activity in conscious dogs."; RS67333, or 1-(4-amino-5-chloro-2-methoxyphenyl)-
3-(1-n-
butyl-4-piperidinyl)-1-propanone; KDR-5169, or 4-amino-5-chloro-N-[1-(3-fluoro-
4-
methoxybenzyl)piperidin-4-yl]-2-(2-hydroxyethoxy)benzamide hydrochloride
dihydrate as
reported by Tazawa, et al. ((2002) "KDR-5169, a new gastrointestinal
prokinetic agent,
enhances gastric contractile and emptying activities in dogs and rats." Eur J
Pharmacol
434(3):169-76); SL65.0155, or 5-(8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-
5-yl)-3-[1-
(2-phenyl ethyl)-4-piperidinyl]-1,3,4-oxadiazol-2(3H)-one monohydrochloride;
and Y-34959,
205
CA 02726300 2010-12-22
or 4-amino-5-chloro-2-methoxy-N-[ 1-[5-(I-methylindol-3-
ylcarbonylamino)pentyl]piperidin-
4-ylmethyl]benzamide.
[04171 Other non-limiting reported 5HT4 receptor agonists and partial agonists
for use in
combination with a 5HTR agent include metoclopramide (CAS RN 364-62-5), 5-
methoxytryptamine (CAS RN 608-07-1), RS67506 (CAS RN 168986-61-6), 2-[1-(4-
piperonyl)piperazinyl]benzothiazole (CAS RN 155106-73-3), RS66331 (see
Buccafusco et
al. "Multiple Central Nervous System Targets for Eliciting Beneficial Effects
on Memory and
Cognition." (2000) Pharmacology 295(2):438-446), BIMU8 (endo-N-8-methyl-8-
azabicyclo[3.2.1 ]oct-3-yl)-2,3-dehydro-2-oxo-3-(prop-2-yl)-1 H-benzimid-azole-
l -
carboxamide), or SB 205149 (the n-butyl quaternary analog of renzapride).
Compounds
related to metoclopramide, such as metoclopramide dihydrochloride (CAS RN 2576-
84-3) or
metoclopramide dihydrochloride (CAS RN 5581-45-3) or metoclopramide
hydrochloride
(CAS RN 7232-21-5 or 54143-57-6) may also be used in a combination or method
as
described herein.
104181 Additionally, a 5HTR agent may be a reported 5HT6 receptor antagonist
such as
SB-357134 (N-(2,5-dibromo-3-fluorophenyl)-4-methoxy-3-piperazin-l-
ylbenzenesulfonamide); SB-271046 (5-chloro-N-(4-methoxy-3-(piperazin-l-
yl)phenyl)-3-
methylbenzo[b]thiophene-2-sulfonamide); Ro 04-06790 (N-(2,6-
bis(methylamino)pyrimidin-
4-yl)-4-aminobenzenesulfonamide); Ro 63-0563 (4-amino-N-(2,6 bis-methylamino-
pyridin-
4-yl)-benzene sulfonamide); clozapine or its metabolite N-desmethylclozapine;
olanzapine
(CAS RN 132539-06-1); fluperlapine (CAS RN 67121-76-0); seroquel (quetiapine
or
quetiapine fumarate); clomipramine (CAS RN 303-49-1); amitriptyline (CAS RN50-
48-6);
doxepin (CAS RN 1668-19-5); nortryptyline (CAS RN 72-69-5); 5-
methoxytryptamine (CAS
RN 608-07-1); bromocryptine (CAS RN 25614-03-3); octoclothepin (CAS RN 13448-
22-1);
chlorpromazine (CAS RN 50-53-3); loxapine (CAS RN 1977-10-2); fluphenazine
(CAS RN
69-23-8); or GSK 742457 (presented by David Witty, "Early Optimisation of in
vivo
Activity: the discovery of 5-HT6 Receptor Antagonist 742457" GlaxoSmithKline
at
SCIpharm 2006, International Pharmaceutical Industry Conference in Edinburgh,
16 May
2006).
104191 As an additional non-limiting example, the reported 5HT6 modulator may
be SB-
258585 (4-Iodo-N-[4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-benzen-
sulphonamide);
PRX 07034 (from Predix Pharmaceuticals) or a partial agonist, such as E-6801
(6-chloro-N-
206
CA 02726300 2010-12-22
(3-(2-(dimethylamino)ethyl)-IH-indol-5-yl)imidazo[2,I-b]thiazole-5-
sulfonamide) or E-6837
(5-chloro-N-(3 -(2-(dimethylamino)ethyl)-1 H-indol-5-yl)naphthalene-2-
sulfonamide).
[0420] A 5HTR agent as described herein includes pharmaceutically acceptable
salts,
derivatives, prodrugs, and metabolites of the agent. Methods for preparing and
administering
salts, derivatives, prodrugs, and metabolites of various agents are well known
in the art.
[0421] Compounds described herein that contain a chiral center include all
possible
stereoisomers of the compound, including compositions comprising the racemic
mixture of
the two enantiomers, as well as compositions comprising each enantiomer
individually,
substantially free of the other enantiomer. Thus, for example, contemplated
herein is a
composition comprising the S enantiomer of a compound substantially free of
the R
enantiomer, or the R enantiomer substantially free of the S enantiomer. If the
named
compound comprises more than one chiral center, the scope of the present
disclosure also
includes compositions comprising mixtures of varying proportions between the
diastereomers, as well as compositions comprising one or more diastereomers
substantially
free of one or more of the other diastereomers. By "substantially free" it is
meant that the
composition comprises less than 25%, 15%, 10%, 8%, 5%, 3%, or less than I% of
the minor
enantiomer or diastereomer(s). Methods for synthesizing, isolating, preparing,
and
administering various stereoisomers are known in the art.
[0422] In some embodiments, a 5HTR agent used in the methods described herein
is
substantially inactive with respect to other receptors, such as muscarinic
receptors, nicotinic
receptors, dopamine receptors, and opioid receptors as non-limiting examples.
104231 As described herein, a 5HTR agent, in combination with one or more
other
neurogenic agents, or anti-astrogenic agent, is administered to an animal or
human subject to
result in neurogenesis. A combination may thus be used to treat a specified
disease, disorder,
or condition.
[0424] Methods for assessing the nature and/or degree of neurogenesis in vivo
and in
vitro, for detecting changes in the nature and/or degree of neurogenesis, for
identifying
neurogenesis modulating agents, for isolating and culturing neural stem cells,
and for
preparing neural stem cells for transplantation or other purposes are
disclosed, for example,
in U.S. Provisional Application No. 60/697,905, and U.S. Publication Nos.
2005/0009742
and 2005/0009847, 20050032702, 2005/0031538, 2005/0004046, 2004/0254152,
207
CA 02726300 2010-12-22
2004/0229291, and 2004/0185429, all of which are herein incorporated by
reference in their
entirety.
Formulations and Doses
104251 In some embodiments of the disclosure, a 5HTR agent, in combination
with one or
more other neurogenic agents, or anti-astrogenic agent, is in the form of a
composition that
includes at least one pharmaceutically acceptable excipient. As used herein,
the term
"pharmaceutically acceptable excipient" includes any excipient known in the
field as suitable
for pharmaceutical application. Suitable pharmaceutical excipients and
formulations are
known in the art and are described, for example, in Remington's Pharmaceutical
Sciences
(19th ed.) (Genarro, ed. (1995) Mack Publishing Co., Easton, Pa.). Preferably,
pharmaceutical carriers are chosen based upon the intended mode of
administration of a
5HTR agent, in combination with one or more other neurogenic agents, or anti-
astrogenic
agent. The pharmaceutically acceptable carrier may include, for example,
disintegrants,
binders, lubricants, glidants, emollients, humectants, thickeners, silicones,
flavoring agents,
and water.
104261 A 5HTR agent, in combination with one or more other neurogenic agents,
or anti-
astrogenic agent, or with another 5HTR agent, may be incorporated with
excipients and
administered in the form of ingestible tablets, buccal tablets, troches,
capsules, elixirs,
suspensions, syrups, wafers, or any other form known in the pharmaceutical
arts. The
pharmaceutical compositions may also be formulated in a sustained release
form. Sustained
release compositions, enteric coatings, and the like are known in the art.
Alternatively, the
compositions may be a quick release formulation.
104271 The amount of a combination of a 5HTR agent, or a combination thereof
with one
or more other neurogenic agents, or anti-astrogenic agent, may be an amount
that also
potentiates or sensitizes, such as by activating or inducing cells to
differentiate, a population
of neural cells for neurogenesis. The degree of potentiation or sensitization
for neurogenesis
may be determined with use of the combination in any appropriate neurogenesis
assay,
including, but not limited to, a neuronal differentiation assay described
herein. In some
embodiments, the amount of a combination of a 5HTR agent, in combination with
one or
more other neurogenic agents, or anti-astrogenic agent, is based on the
highest amount of one
agent in a combination, which amount produces no detectable neuroproliferation
in vitro but
208
CA 02726300 2010-12-22
yet produces neurogenesis, or a measurable shift in efficacy in promoting
neurogenesis in
vitro, when used in the combination.
[04281 As disclosed herein, an effective amount of a 5HTR agent, in
combination with
one or more other neurogenic agents, or anti-astrogenic agent, in the
described methods is an
amount sufficient, when used as described herein, to stimulate or increase
neurogenesis in the
subject targeted for treatment when compared to the absence of the
combination. An
effective amount of a 5HTR agent alone or in combination may vary based on a
variety of
factors, including but not limited to, the activity of the active compounds,
the physiological
characteristics of the subject, the nature of the condition to be treated, and
the route and/or
method of administration. General dosage ranges of certain compounds are
provided herein
and in the cited references based on animal models of CNS diseases and
conditions. Various
conversion factors, formulas, and methods for determining human dose
equivalents of animal
dosages are known in the art, and are described, e.g., in Freireich et al.,
Cancer Chemother
Repts 50(4): 219 (1966), Monro et al., Toxicology Pathology, 23: 187-98
(1995),
Boxenbaum and Dilea, J.Clin.Pharmacol. 35: 957-966 (1995), and Voisin et al.,
Reg.
Toxicol. Pharmacol., 12(2): 107-116 (1990), which are herein incorporated by
reference.
104291 The disclosed methods typically involve the administration of a 5HTR
agent, in
combination with one or more other neurogenic agents, or anti-astrogenic
agent, in a dosage
range of from about 0.001 ng/kg/day to about 200 mg/kg/day. Other non-limiting
dosages
include from about 0.001 to about 0.01 ng/kg/day, about 0.01 to about 0.1
ng/kg/day, about
0.1 to about 1 ng/kg/day, about 1 to about 10 ng/kg/day, about 10 to about 100
ng/kg/day,
about 100 ng/kg/day to about 1 ^ g/kg/day, about 1 to about 2 ^ g/kg/day,
about 2 ^ g/kg/day
to about 0.02 mg/kg/day, about 0.02 to about 0.2 mg/kg/day, about 0.2 to about
2 mg/kg/day,
about 2 to about 20 mg/kg/day, or about 20 to about 200 mg/kg/day. However, as
understood
by those skilled in the art, the exact dosage of a 5HTR agent, in combination
with one or
more other neurogenic agents, or anti-astrogenic agent, used to treat a
particular condition
will vary in practice due to a wide variety of factors. Accordingly, dosage
guidelines
provided herein are not limiting as the range of actual dosages, but rather
provide guidance to
skilled practitioners in selecting dosages useful in the empirical
determination of dosages for
individual patients. Advantageously, methods described herein allow treatment
of one or
more conditions with reductions in side effects, dosage levels, dosage
frequency, treatment
duration, safety, tolerability, and/or other factors. So where suitable
dosages for a 5HTR
209
CA 02726300 2010-12-22
agent to modulate a 5HT receptor activity are known to a skilled person, the
disclosure
includes the use of about 75%, about 50%, about 33%, about 25%, about 20%,
about 15%,
about 10%, about 5%, about 2.5%, about 1%, about 0.5%, about 0.25%, about
0.2%, about
0.1%, about 0.05%, about 0.025%, about 0.02%, about 0.01%, or less than the
known dosage.
[04301 In other embodiments, the amount of a 5HTR agent used in vivo may be
about
50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about
18%,
about 16%, about 14%, about 12%, about 10%, about 8%, about 6%, about 4%,
about 2%, or
about I% or less than the maximum tolerated dose for a subject, including
where one or more
other neurogenic agents, or anti-astrogenic agent is used in combination with
the 5HTR
agent. This is readily determined for each muscarinic agent that has been in
clinical use or
testing, such as in humans.
104311 Alternatively, the amount of a 5HTR agent, in combination with one or
more other
neurogenic agents, or anti-astrogenic agent, may be an amount selected to be
effective to
produce an improvement in a treated subject based on detectable neurogenesis
in vitro as
described above. In some embodiments, such as in the case of a known 5HTR
agent, the
amount is one that minimizes clinical side effects seen with administration of
the agent to a
subject. The amount of an agent used in vivo may be about 50%, about 45%,
about 40%,
about 35%, about 30%, about 25%, about 20%, about 18%, about 16%, about 14%,
about
12%, about 10%, about 8%, about 6%, about 4%, about 2%, or about I% or less of
the
maximum tolerated dose in terms of acceptable side effects for a subject. This
is readily
determined for each 5HTR agent or other agent(s) of a combination disclosed
herein as well
as those that have been in clinical use or testing, such as in humans.
104321 In other embodiments, the amount of an additional neurogenic
sensitizing agent in
a combination with a 5HTR agent of the disclosure is the highest amount which
produces no
detectable neurogenesis when the sensitizing agent is used, alone in vitro, or
in vivo, but yet
produces neurogenesis, or a measurable shift in efficacy in promoting
neurogenesis, when
used in combination with a 5HTR agent. Embodiments include amounts which
produce
about 1%, about 2%, about 4%, about 6%, about 8%, about 10%, about 12%, about
14%,
about 16%, about 18%, about 20%, about 25%, about 30%, about 35%, or about 40%
or more
of the neurogenesis seen with the amount that produces the highest level of
neurogenesis in
an in vitro assay.
210
CA 02726300 2010-12-22
[0433] In some embodiments, the amount may be the lowest needed to produce a
desired,
or minimum, level of detectable neurogenesis or beneficial effect. Of course
the
administered 5HTR agent, alone or in a combination disclosed herein, may be in
the form of
a pharmaceutical composition.
[0434] As described herein, the amount of a 5HTR agent, in combination with
one or
more other neurogenic agents, or anti-astrogenic agent, may be any that is
effective to
produce neurogenesis, optionally with reduced or minimized amounts of
astrogenesis. As a
non-limiting example described herein, the levels of astrogenesis observed
with the use of
certain 5HTR agents alone may be reduced or suppressed when the 5HTR agent is
used in
combination with a second agent such as baclofen (or other GABA modulator with
the same
anti-astrogenesis activity) or melatonin. This beneficial effect is observed
along with the
ability of each combination of agents to stimulate neurogenesis. So while
certain 5HTR
agents have been observed to produce astrogenesis, their use with a second
compound, such
as baclofen and melatonin, advantageously provides a means to suppress the
overall level of
astrogenesis.
[0435] Therefore, the methods of the disclosure further include a method of
decreasing the
level of astrogenesis in a cell or cell population by contacting the cell or
population with a
5HTR agent and a second agent that reduces or suppresses the amount or level
of
astrogenesis caused by said 5HTR agent. The reduction or suppression of
astrogenesis may
be readily determined relative to the amount or level of astrogenesis in the
absence of the
second agent. In some embodiments, the second agent is baclofen or melatonin.
[0436] In some embodiments, an effective, neurogenesis modulating amount of a
combination of a 5HTR agent, in combination with one or more other neurogenic
agents, or
anti-astrogenic agent, is an amount of a 5HTR agent (or of each agent in a
combination) that
achieves a concentration within the target tissue, using the particular mode
of administration,
at or above the IC50 or EC50 for activity of target molecule or physiological
process. In some
cases, a 5HTR agent, in combination with one or more other neurogenic agents,
or anti-
astrogenic agent, is administered in a manner and dosage that gives a peak
concentration of
about 1, about 1.5, about 2, about 2.5, about 5, about 10, about 20 or more
times the IC50 or
EC50 concentration of the 5HTR agent (or each agent in the combination). IC50
and EC50
values and bioavailability data for a 5HTR agent and other agent(s) described
herein are
known in the art, and are described, e.g., in the references cited herein or
can be readily
211
CA 02726300 2010-12-22
determined using established methods. In addition, methods for determining the
concentration of a free compound in plasma and extracellular fluids in the
CNS, as well
pharmacokinetic properties, are known in the art, and are described, e.g., in
de Lange et al.,
AAPS Journal, 7(3): 532-543 (2005). In some embodiments, a 5HTR agent, in
combination
with one or more other neurogenic agents, or anti-astrogenic agent, described
herein is
administered, as a combination or separate agents used together, at a
frequency of at least
about once daily, or about twice daily, or about three or more times daily,
and for a duration
of at least about 3 days, about 5 days, about 7 days, about 10 days, about 14
days, or about 21
days, or about 4 weeks, or about 2 months, or about 4 months, or about 6
months, or about 8
months, or about 10 months, or about 1 year, or about 2 years, or about 4
years, or about 6
years or longer.
[0437] In other embodiments, an effective, neurogenesis modulating amount is a
dose that
produces a concentration of a 5HTR agent (or each agent in a combination) in
an organ,
tissue, cell, and/or other region of interest that includes the ED50 (the
pharmacologically
effective dose in 50% of subjects) with little or no toxicity. IC50 and EC50
values for the
modulation of neurogenesis can be determined using methods described in PCT
Application
US06/026677, filed July 7, 2006, incorporated by reference, or by other
methods known in
the art. In some embodiments, the IC50 or EC50 concentration for the
modulation of
neurogenesis is substantially lower than the IC50 or EC50 concentration for
activity of a 5HTR
agent and/or other agent(s) at non-targeted molecules and/or physiological
processes.
104381 In some methods described herein, the application of a 5HTR agent in
combination
with one or more other neurogenic agents, or anti-astrogenic agent may allow
effective
treatment with substantially fewer and/or less severe side effects compared to
existing
treatments. In some embodiments, combination therapy with a 5HTR agent and one
or more
additional neurogenic agents allows the combination to be administered at
dosages that would
be sub-therapeutic when administered individually or when compared to other
treatments. In
other embodiments, each agent in a combination of agents may be present in an
amount that
results in fewer and/or less severe side effects than that which occurs with a
larger amount.
Thus the combined effect of the neurogenic agents will provide a desired
neurogenic activity
while exhibiting fewer and/or less severe side effects overall. In further
embodiments,
methods described herein allow treatment of certain conditions for which
treatment with the
212
CA 02726300 2010-12-22
same or similar compounds is ineffective using known methods due, for example,
to dose-
limiting side effects, toxicity, and/or other factors.
Routes ofAdministration
[04391 As described, the methods of the disclosure comprise contacting a cell
with a
5HTR agent, in combination with one or more other neurogenic agents, or anti-
astrogenic
agent, or administering such an agent or combination to a subject, to result
in neurogenesis.
Some embodiments comprise the use of one 5HTR agent, such as buspirone,
tandospirone,
azasetron, granisetron, ondansetron, mosapride, cisapride, or sumatriptan, in
combination
with one or more other neurogenic agents, or anti-astrogenic agent. In other
embodiments, a
combination of two or more agents, such as two or more of buspirone,
tandospirone,
azasetron, granisetron, ondansetron, mosapride, cisapride, and sumatriptan, is
used in
combination with one or more other neurogenic agents, or anti-astrogenic
agent.
[04401 In some embodiments, methods of treatment disclosed herein comprise the
step of
administering to a mammal a 5HTR agent, in combination with one or more other
neurogenic
agents, or anti-astrogenic agent, for a time and at a concentration sufficient
to treat the
condition targeted for treatment. The disclosed methods can be applied to
individuals having,
or who are likely to develop, disorders relating to neural degeneration,
neural damage and/or
neural demyelination.
[04411 Depending on the desired clinical result, the disclosed agents or
pharmaceutical
compositions are administered by any means suitable for achieving a desired
effect. Various
delivery methods are known in the art and can be used to deliver an agent to a
subject or to
NSCs or progenitor cells within a tissue of interest. The delivery method will
depend on
factors such as the tissue of interest, the nature of the compound (e.g., its
stability and ability
to cross the blood-brain barrier), and the duration of the experiment or
treatment, among
other factors. For example, an osmotic minipump can be implanted into a
neurogenic region,
such as the lateral ventricle. Alternatively, compounds can be administered by
direct
injection into the cerebrospinal fluid of the brain or spinal column, or into
the eye.
Compounds can also be administered into the periphery (such as by intravenous
or
subcutaneous injection, or oral delivery), and subsequently cross the blood-
brain barrier.
104421 In some embodiments, the disclosed agents or pharmaceutical
compositions are
administered in a manner that allows them to contact the subventricular zone
(SVZ) of the
213
CA 02726300 2010-12-22
lateral ventricles and/or the dentate gyrus of the hippocampus. The delivery
or targeting of a
5HTR agent, in combination with one or more other neurogenic agents, or anti-
astrogenic
agent, to a neurogenic region, such as the dentate gyrus or the subventricular
zone, may
enhances efficacy and reduces side effects compared to known methods involving
administration with the same or similar compounds. Examples of routes of
administration
include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g.,
inhalation),
transdermal (topical), transmucosal, and rectal administration. Intranasal
administration
generally includes, but is not limited to, inhalation of aerosol suspensions
for delivery of
compositions to the nasal mucosa, trachea and bronchioli.
[04431 In other embodiments, a combination of a 5HTR agent, in combination
with one or
more other neurogenic agents, or anti-astrogenic agent, is administered so as
to either pass
through or by-pass the blood-brain barrier. Methods for allowing factors to
pass through the
blood-brain barrier are known in the art, and include minimizing the size of
the factor,
providing hydrophobic factors which facilitate passage, and conjugation to a
carrier molecule
that has substantial permeability across the blood brain barrier. In some
instances, an agent
or combination of agents can be administered by a surgical procedure
implanting a catheter
coupled to a pump device. The pump device can also be implanted or be
extracorporally
positioned. Administration of a 5HTR agent, in combination with one or more
other
neurogenic agents, or anti-astrogenic agent, can be in intermittent pulses or
as a continuous
infusion. Devices for injection to discrete areas of the brain are known in
the art. In certain
embodiments, the combination is administered locally to the ventricle of the
brain, substantia
nigra, striatum, locus ceruleous, nucleus basalis of Meynert, pedunculopontine
nucleus,
cerebral cortex, and/or spinal cord by, e.g., injection. Methods,
compositions, and devices for
delivering therapeutics, including therapeutics for the treatment of diseases
and conditions of
the CNS and PNS, are known in the art.
[04441 In some embodiments, a 5HTR agent and/or other agent(s) in a
combination is
modified to facilitate crossing of the gut epithelium. For example, in some
embodiments, a
5HTR agent or other agent(s) is a prodrug that is actively transported across
the intestinal
epithelium and metabolized into the active agent in systemic circulation
and/or in the CNS.
[04451 In other embodiments, a 5HTR agent and/or other agent(s) of a
combination is
conjugated to a targeting domain to form a chimeric therapeutic, where the
targeting domain
facilitates passage of the blood-brain barrier (as described above) and/or
binds one or more
214
CA 02726300 2010-12-22
molecular targets in the CNS. In some embodiments, the targeting domain binds
a target that
is differentially expressed or displayed on, or in close proximity to,
tissues, organs, and/or
cells of interest. In some cases, the target is preferentially distributed in
a neurogenic region
of the brain, such as the dentate gyrus and/or the SVZ. For example, in some
embodiments, a
5HTR agent and/or other agent(s) of a combination is conjugated or complexed
with the fatty
acid docosahexaenoic acid (DHA), which is readily transported across the blood
brain barrier
and imported into cells of the CNS.
Representative Conditions and Agents
[0446] The disclosure includes methods for treating affective disorder and
other
neurological diseases and conditions. In some embodiments, a method may
comprise use of
a combination of a 5HTR agent and one or more agents reported as anti-
depressant agents.
Thus a method may comprise treatment with a 5HTR agent and one or more
reported anti-
depressant agents as known to the skilled person. Non-limiting examples of
such agents
include an SSRI (selective serotonine reuptake inhibitor), such as fluoxetine
(Prozac ;
described, e.g., in U.S. Pat. 4,314,081 and 4,194,009), citalopram (Celexa ;
described, e.g.,
in U.S. Pat. 4,136,193), escitalopram (Lexapro ; described, e.g., in U.S. Pat.
4,136,193),
fluvoxamine (described, e.g., in U.S. Pat. 4,085,225) or fluvoxamine maleate
(CAS RN:
61718-82-9) and Luvox , paroxetine (Paxil ; described, e.g., in U.S. Pat.
3,912,743 and
4,007,196), or sertraline (Zoloft ; described, e.g., in U.S. Pat. 4,536,518),
or alaproclate; the
compound nefazodone (Serozone ; described, e.g., in U.S. Pat. 4,338,317); a
selective
norepinephrine reuptake inhibitor (SNRI) such as reboxetine (Edronax ),
atomoxetine
(Strattera ), milnacipran (described, e.g., in U.S. Pat. 4,478,836),
sibutramine or its primary
amine metabolite (BTS 54 505), amoxapine, or maprotiline; a selective
serotonin and
norepinephrine reuptake inhibitor (SSNRI) such as venlafaxine (Effexor(&;
described, e.g., in
U.S. Pat. 4,761,501), and its reported metabolite desvenlafaxine, or
duloxetine (Cymbalta ;
described, e.g., in U.S. Pat. 4,956,388); a serotonin, noradrenaline, and
dopamine "triple
uptake inhibitor", such as
DOV 102,677 (see Popik et al. "Pharmacological Profile of the "Triple"
Monoamine
Neurotransmitter Uptake Inhibitor, DOV 102,677." Cell Mol Neurobiol. 2006 Apr
25; Epub
ahead of print),
DOV 216,303 (see Beer et al. "DOV 216,303, a "triple" reuptake inhibitor:
safety,
tolerability, and pharmacokinetic profile." J Clin Pharmacol. 2004 44(12):1360-
7),
215
CA 02726300 2010-12-22
DOV 21,947 ((+)-1-(3,4-dichlorophenyl)-3-azabicyclo-(3.1.0)hexane
hydrochloride),
see Skolnick et al. "Antidepressant-like actions of DOV 21,947: a "triple"
reuptake
inhibitor." Eur J Pharmacol. 2003 461(2-3):99-104),
NS-2330 or tesofensine (CAS RN 402856-42-2), or NS 2359 (CAS RN 843660-54-
8);
and agents like dehydroepiandrosterone (DHEA), and DHEA sulfate (DHEAS), CP-
122,721 (CAS RN 145742-28-5).
[0447] Additional non-limiting examples of such agents include a tricyclic
compound
such as clomipramine, dosulepin or dothiepin, lofepramine (described, e.g., in
U.S. Pat.
4,172,074), trimipramine, protriptyline, amitriptyline, desipramine(described,
e.g., in U.S.
Pat. 3,454,554), doxepin, imipramine, or nortriptyline; a psychostimulant such
as
dextroamphetamine and methylphenidate; an MAO inhibitor such as selegiline
(Emsam );
an ampakine such as CX516 (or Ampalex , CAS RN: 154235-83-3), CX546 (or 1-(1,4-
benzodioxan-6-ylcarbonyl)piperidine), and CX614 (CAS RN 191744-13-5) from
Cortex
Pharmaceuticals; a Vlb antagonist such as SSR149415 ((2S,4R)-1-[5-chloro-l-
[(2,4-
dimethoxyphenyl)sulfonyl]-3 -(2-methoxy-phenyl)-2-oxo-2,3 -dihydro-1 H-indol-3
-yl]-4-
hydroxy-N,N-dimethyl-2-pyrrolidine carboxamide),
[I -(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid), 2-0-
ethyltyrosine,
4-valine] arginine vasopressin (d(CH2)5[Tyr(Et2)]VAVP (WK 1-1),
9-desglycine[1-(beta-mercapto-beta,beta- cyclopentamethylenepropionic acid), 2-
0-
ethyltyrosine, 4-valine] arginine vasopressin desGly9d(CH2)5 [Tyr(Et2)]-VAVP
(WK 3-6), or
9-desglycine [I -(beta-mercapto-beta,beta- cyclopentamethylenepropionic
acid),2-D-
(O-ethyl)tyrosine, 4-valine ] arginine vasopressin des Gly9d(CH2)5[D-
Tyr(Et2)]VAVP (AO
3-21); a corticotropin-releasing factor receptor (CRF) R antagonist such as CP-
154,526
(structure disclosed in Schulz et al. "CP-1 54,526: a potent and selective
nonpeptide
antagonist of corticotropin releasing factor receptors." Proc Natl Acad Sci U
S A. 1996
93(19):10477-82), NBI 30775 (also known as R121919 or 2,5-dimethyl-3-(6-
dimethyl-4-
methylpyridin-3-yl)-7-dipropylaminopyrazolo[1,5-a]pyrimidine), astressin (CAS
RN 170809-
51-5), or a photoactivatable analog thereof as described in Bonk et al. "Novel
high-affinity
photoactivatable antagonists of corticotropin-releasing factor (CRF)" Eur. J.
Biochem.
267:3017-3024 (2000), or AAG561 (from Novartis); a melanin concentrating
hormone
(MCH) antagonist such as 3,5-dimethoxy-N-(1-(naphthalen-2-ylmethyl)piperidin-4-
yl)benzamide or (R)-3,5-dimethoxy-N-(I-(naphthalen-2-ylmethyl)-pyrrolidin-3-
yl)benzamide
216
CA 02726300 2010-12-22
(see Kim et al. "Identification of substituted 4-aminopiperidines and 3-
aminopyrrolidines as
potent MCH-R1 antagonists for the treatment of obesity." Bioorg Med Chem Lett.
2006 Jul
29; [Epub ahead of print] for both), or any MCH antagonist disclosed in U.S.
Patent
7,045,636 or published U.S. Patent Application US2005/0171098.
[0448] Further non-limiting examples of such agents include a tetracyclic
compound such
as mirtazapine (described, e.g., in U.S. Pat. 4,062,848; see CAS RN 61337-67-
5; also known
as Remeron , or CAS RN 85650-52-8), mianserin (described, e.g., in U.S. Pat.
3,534,041),
or setiptiline.
[0449] Further non-limiting examples of such agents include agomelatine (CAS
RN
138112-76-2), pindolol (CAS RN 13523-86-9), antalarmin (CAS RN 157284-96-3),
mifepristone (CAS RN 84371-65-3), nemifitide (CAS RN 173240-15-8) or
nemifitide
ditriflutate (CAS RN 204992-09-6), YKP-lOA or R228060 (CAS RN 561069-23-6),
trazodone (CAS RN 19794-93-5), bupropion (CAS RN 34841-39-9 or 34911-55-2) or
bupropion hydrochloride (or Wellbutrin , CAS RN 31677-93-7) and its reported
metabolite
radafaxine (CAS RN 192374-14-4), NS2359 (CAS RN 843660-54-8), Org 34517 (CAS
RN
189035-07-2), Org 34850 (CAS RN 162607-84-3), vilazodone (CAS RN 163521-12-8),
CP-
122,721 (CAS RN 145742-28-5), gepirone (CAS RN 83928-76-1), SR58611 (see
Mizuno et
al. "The stimulation of beta(3)-adrenoceptor causes phosphorylation of
extracellular signal-
regulated kinases 1 and 2 through a G(s)- but not G(i)-dependent pathway in
3T3-L1
adipocytes." Eur J Pharmacol. 2000 404(1-2):63-8), saredutant or SR 48968 (CAS
RN
142001-63-6), PRX-00023 (N-{3-[4-(4-
cyclohexylmethanesulfonylaminobutyl)piperazin-1-
yl]phenyl}acetamide, see Becker et al. "An integrated in silico 3D model-
driven discovery of
a novel, potent, and selective amidosulfonamide 5-HT1A agonist (PRX-00023) for
the
treatment of anxiety and depression." J Med Chem. 2006 49(11):3116-35),
vestipitant (or
GW597599, CAS RN 334476-46-9), OPC-14523 or VPI-013 (see Bermack et al.
"Effects of
the potential antidepressant OPC-14523 [1-[3-[4-(3-chlorophenyl)-1-
piperazinyl]propyl]-5-
methoxy-3,4-dihydro-2-quinolinone monomethanesulfonate] a combined sigma and 5-
HTIA
ligand: modulation of neuronal activity in the dorsal raphe nucleus." J
Pharmacol Exp Ther.
2004 310(2):578-83), casopitant or GW679769 (CAS RN 852393-14-7), elzasonan or
CP-
448,187 (CAS RN 361343-19-3), GW823296 (see published U.S. Patent Application
US2005/0119248), delucemine or NPS 1506 (CAS RN 186495-49-8), or ocinaplon
(CAS RN
96604-21-6).
217
CA 02726300 2010-12-22
[04501 Yet additional non-limiting examples of such agents include CX717 from
Cortex
Pharmaceuticals, TGBAO I AD (a serotonin reuptake inhibitor, 5-HT2 agonist, 5-
HT 1 A
agonist, and 5-HT 1 D agonist) from Fabre-Kramer Pharmaceuticals, Inc., ORG
4420 (an
NaSSA (noradrenergic/specific serotonergic antidepressant) from Organon, CP-
316,311 (a
CRF 1 antagonist) from Pfizer, BMS-562086 (a CRF 1 antagonist) from Bristol-
Myers Squibb,
GW876008 (a CRF1 antagonist) from Neurocrine/GlaxoSmithKline, ONO-2333Ms (a
CRFI
antagonist) from Ono Pharmaceutical Co., Ltd., JNJ-19567470 or TS-041 (a CRF1
antagonist) from Janssen (Johnson & Johnson) and Taisho, SSR 125543 or SSR
126374 (a
CRF1 antagonist) from Sanofi-Aventis, Lu AA21004 and Lu AA24530 (both from H.
Lundbeck A/S), SEP-225289 from Sepracor Inc., ND7001 (a PDE2 inhibitor) from
Neuro3d,
SSR 411298 or SSR 101010 (a fatty acid amide hydrolase, or FAAH, inhibitor)
from Sanofi-
Aventis, 163090 (a mixed serotonin receptor inhibitor) from GlaxoSmithKline,
SSR 241586
(an NK2 and NK3 receptor antagonist) from Sanofi-Aventis, SAR 102279 (an NK2
receptor
antagonist) from Sanofi-Aventis, YKP581 from SK Pharmaceuticals (Johnson &
Johnson),
R1576 (a GPCR modulator) from Roche, or ND1251 (a PDE4 inhibitor) from
Neuro3d.
[04511 In other embodiments, a method may comprise use of a combination of a
5HTR
agent and one or more agents reported as anti-psychotic agents. Non-limiting
examples of a
reported anti-psychotic agent as a member of a combination include olanzapine,
quetiapine
(Seroquel ), clozapine (CAS RN 5786-21-0) or its metabolite ACP-104 (N-
desmethylclozapine or norclozapine, CAS RN 6104-71-8), reserpine,
aripiprazole,
risperidone, ziprasidone, sertindole, trazodone, paliperidone (CAS RN 144598-
75-4),
mifepristone (CAS RN 84371-65-3), bifeprunox or DU-127090 (CAS RN 350992-10-
8),
asenapine or ORG 5222 (CAS RN 65576-45-6), iloperidone (CAS RN 133454-47-4),
ocaperidone (CAS RN 129029-23-8), SLV 308 (CAS RN 269718-83-4), licarbazepine
or GP
47779 (CAS RN 29331-92-8), Org 34517 (CAS RN 189035-07-2), ORG 34850 (CAS RN
162607-84-3), Org 24448 (CAS RN 211735-76-1), lurasidone (CAS RN 367514-87-2),
blonanserin or lonasen (CAS RN 132810-10-7), talnetant or SB-223412 (CAS RN
174636-
32-9), secretin (CAS RN 1393-25-5) or human secretin (CAS RN 108153-74-8)
which are
endogenous pancreatic hormones, ABT 089 (CAS RN 161417-03-4), SSR 504734 (see
compound 13 in Hashimoto "Glycine Transporter Inhibitors as Therapeutic Agents
for
Schizophrenia." Recent Patents on CNS Drug Discovery, 2006 1:43-53), MEM 3454
(see
Mazurov et al. "Selective alpha7 nicotinic acetylcholine receptor ligands."
Curr Med Chem.
2006 13(13):1567-84), a phosphodiesterase 10A (PDEI OA) inhibitor such as
papaverine
218
CA 02726300 2010-12-22
(CAS RN 58-74-2) or papaverine hydrochloride (CAS RN 61-25-6), paliperidone
(CAS RN
144598-75-4), trifluoperazine (CAS RN 117-89-5), or trifluoperazine
hydrochloride (CAS
RN 440-17-5).
[0452] Additional non-limiting examples of such agents include
trifluoperazine,
fluphenazine, chlorpromazine, perphenazine, thioridazine, haloperidol,
loxapine,
mesoridazine, molindone, pimoxide, or thiothixene, SSR 146977 (see Emonds-Alt
et al.
"Biochemical and pharmacological activities of SSR 146977, a new potent
nonpeptide
tachykinin NK3 receptor antagonist." Can J Physiol Pharmacol. 2002 80(5):482-
8),
SSR181507 ((3-exo)-8-benzoyl-N-[[(2 s)7-chloro-2,3-dihydro-1,4-benzodioxin-1-
yl]methyl]-
8-azabicyclo[3.2.1]octane-3-methanamine monohydrochloride), or SLV313 (1-(2,3-
dihydro-
benzo[ 1,4]dioxin-5-yl)-4-[5-(4-fluorophenyl)-pyridin-3-ylmethyl]-piperazine).
[04531 Further non-limiting examples of such agents include Lu-35-138 (a D4/5-
HT
antagonist) from Lundbeck, AVE 1625 (a CBI antagonist) from Sanofi-Aventis,
SLV
310,313 (a 5-HT2A antagonist) from Solvay, SSR 181507 (a D2/5-HT2 antagonist)
from
Sanofi-Aventis, GW07034 (a 5-HT6 antagonist) or GW773812 (a D2, 5-HT
antagonist) from
GlaxoSmithKline, YKP 1538 from SK Pharmaceuticals, SSR 125047 (a sigma
receptor
antagonist) from Sanofi-Aventis, MEM1003 (a L-type calcium channel modulator)
from
Memory Pharmaceuticals, JNJ-17305600 (a GLYT1 inhibitor) from Johnson &
Johnson, XY
2401 (a glycine site specific NMDA modulator) from Xytis, PNU 170413 from
Pfizer, RGH-
188 (a D2, D3 antagonist) from Forrest, SSR 180711 (an alpha7 nicotinic
acetylcholine
receptor partial agonist) or SSR 103800 (a GLYT1 (Type 1 glycine transporter)
inhibitor) or
SSR 241586 (a NK3 antagonist) from Sanofi-Aventis.
[04541 In other disclosed embodiments, a reported anti-psychotic agent may be
one used
in treating schizophrenia. Non-limiting examples of a reported anti-
schizophrenia agent as a
member of a combination with a 5HTR agent include molindone hydrochloride
(MOBAN )
and TC-1827 (see Bohme et al. "In vitro and in vivo characterization of TC-
1827, a novel
brain a402 nicotinic receptor agonist with pro-cognitive activity." Drug
Development
Research 2004 62(1):26-40).
104551 In some embodiments, a method may comprise use of a combination of a
5HTR
agent and one or more agents reported for treating weight gain, metabolic
syndrome, or
obesity, and/or to induce weight loss or prevent weight gain. Non-limiting
examples of the
219
CA 02726300 2010-12-22
reported agent include various diet pills that are commercially or clinically
available. In
some embodiments, the reported agent is orlistat (CAS RN 96829-58-2),
sibutramine (CAS
RN 106650-56-0) or sibutramine hydrochloride (CAS RN 84485-00-7), phetermine
(CAS
RN 122-09-8) or phetermine hydrochloride (CAS RN 1197-21-3), diethylpropion or
amfepramone (CAS RN 90-84-6) or diethylpropion hydrochloride, benzphetamine
(CAS RN
156-08-1) or benzphetamine hydrochloride, phendimetrazine (CAS RN 634-03-7 or
21784-
30-5) or phendimetrazine hydrochloride (CAS RN 17140-98-6) or phendimetrazine
tartrate,
rimonabant (CAS RN 168273-06-1), bupropion hydrochloride (CAS RN: 31677-93-7),
topiramate (CAS RN 97240-79-4), zonisamide (CAS RN 68291-97-4), or APD-356
(CAS
RN 846589-98-8).
[0456] In other non-limiting embodiments, the agent may be fenfluramine or
Pondimin
(CAS RN 458-24-2), dexfenfluramine or Redux (CAS RN 3239-44-9), or
levofenfluramine
(CAS RN 37577-24-5); or a combination thereof or a combination with
phentermine. Non-
limiting examples include a combination of fenfluramine and phentermine (or
"fen-phen")
and of dexfenfluramine and phentermine (or "dexfen-phen").
[0457] The combination therapy may be of one of the above with a 5HTR agent as
described herein to improve the condition of the subject or patient. Non-
limiting examples of
combination therapy include the use of lower dosages of the above additional
agents, or
combinations thereof, which reduce side effects of the agent or combination
when used alone.
For example, an anti-depressant agent like fluoxetine or paroxetine or
sertraline may be
administered at a reduced or limited dose, optionally also reduced in
frequency of
administration, in combination with a 5HTR agent.
[0458] Similarly, a combination of fenfluramine and phentermine, or
phentermine and
dexfenfluramine, may be administered at a reduced or limited dose, optionally
also reduced
in frequency of administration, in combination with a 5HTR agent. The reduced
dose or
frequency may be that which reduces or eliminates the side effects of the
combination.
[0459] In light of the positive recitation (above and below) of combinations
with
alternative agents to treat conditions disclosed herein, the disclosure
includes embodiments
with the explicit exclusion of one or more of the alternative agents or one or
more types of
alternative agents. As would be recognized by the skilled person, a
description of the whole
of a plurality of alternative agents (or classes of agents) necessarily
includes and describes
220
CA 02726300 2010-12-22
subsets of the possible alternatives, such as the part remaining with the
exclusion of one or
more of the alternatives or exclusion of one or more classes.
Representative Combinations
[04601 As indicated herein, the disclosure includes combination therapy, where
a 5HTR
agent in combination with one or more other neurogenic agents, or anti-
astrogenic agent is
used to produce neurogenesis. When administered as a combination, the
therapeutic
compounds can be formulated as separate compositions that are administered at
the same
time or sequentially at different times, or the therapeutic compounds can be
given as a single
composition. The methods of the disclosure are not limited in the sequence of
administration.
104611 Instead, the disclosure includes methods wherein treatment with a 5HTR
agent and
another neurogenic agent occurs over a period of more than about 48 hours,
more than about
72 hours, more than about 96 hours, more than about 120 hours, more than about
144 hours,
more than about 7 days, more than about 9 days, more than about 11 days, more
than about
14 days, more than about 21 days, more than about 28 days, more than about 35
days, more
than about 42 days, more than about 49 days, more than about 56 days, more
than about 63
days, more than about 70 days, more than about 77 days, more than about 12
weeks, more
than about 16 weeks, more than about 20 weeks, or more than about 24 weeks or
more. In
some embodiments, treatment by administering a 5HTR agent, occurs at least
about 12 hours,
such as at least about 24, or at least about 36 hours, before administration
of another
neurogenic agent. Following administration of a 5HTR agent, further
administrations may be
of only the other neurogenic agent in some embodiments of the disclosure. In
other
embodiments, further administrations may be of only the 5HTR agent.
104621 In some cases, combination therapy with a 5HTR agent and one or more
additional
agents results in a enhanced efficacy, safety, therapeutic index, and/or
tolerability, and/or
reduced side effects (frequency, severity, or other aspects), dosage levels,
dosage frequency,
and/or treatment duration. Examples of compounds useful in combinations
described herein
are provided above and below. Structures, synthetic processes, safety
profiles, biological
activity data, methods for determining biological activity, pharmaceutical
preparations, and
methods of administration relating to the compounds are known in the art
and/or provided in
the cited references, all of which are herein incorporated by reference in
their entirety.
Dosages of compounds administered in combination with a 5HTR agent can be,
e.g., a
dosage within the range of pharmacological dosages established in humans, or a
dosage that
221
CA 02726300 2010-12-22
is a fraction of the established human dosage, e.g., 70%, 50%, 30%, 10%, or
less than the
established human dosage.
[0463] In some embodiments, the neurogenic agent combined with a 5HTR agent
may be
a reported opioid or non-opioid (acts independently of an opioid receptor)
agent. In some
embodiments, the neurogenic agent is one reported as antagonizing one or more
opioid
receptors or as an inverse agonist of at least one opioid receptor. A opioid
receptor
antagonist or inverse agonist may be specific or selective (or alternatively
non-specific or
non-selective) for opioid receptor subtypes. So an antagonist may be non-
specific or non-
selective such that it antagonizes more than one of the three known opioid
receptor subtypes,
identified as OP1, OP2, and OP3 (also know as delta, or ^, kappa, or ^, and
mu, or ^,
respectively). Thus an opioid that antagonizes any two, or all three, of these
subtypes, or an
inverse agonist that is specific or selective for any two or all three of
these subtypes, may be
used as the neurogenic agent in the practice. Alternatively, an antagonist or
inverse agonist
may be specific or selective for one of the three subtypes, such as the kappa
subtype as a non-
limiting example.
[0464] Non-limiting examples of reported opioid antagonists include
naltrindol, naloxone,
naloxene, naltrexone, JDTic (Registry Number 785835-79-2; also known as 3-
isoquinolinecarboxamide, 1,2,3,4-tetrahydro-7-hydroxy-N-[(1 S)-1-[[(3R,4R)-4-
(3-
hydroxyphenyl)-3,4-dimethyl-l-piperidinyl]methyl]-2-methylpropyl]-
dihydrochloride, (3R)-
(9CI)), nor-binaltorphimine, and buprenorphine. In some embodiments, a
reported selective
kappa opioid receptor antagonist compound, as described in US 20020132828,
U.S. Patent
6,559,159, and/or WO 2002/053533, may be used. All three of these documents
are herein
incorporated by reference in their entireties as if fully set forth. Further
non-limiting
examples of such reported antagonists is a compound disclosed in U.S. Patent
6,900,228
(herein incorporated by reference in its entirety), arodyn
(Ac[Phe(1,2,3),Arg(4),d-Ala(8)]Dyn
A-(1-11)NH(2), as described in Bennett, et al. (2002) J. Med. Chem. 45:5617-
5619), and an
active analog of arodyn as described in Bennett e al. (2005) J Pept Res.
65(3):322-32,
alvimopan.
[0465] In some embodiments, the neurogenic agent used in the methods described
herein
has "selective" activity (such as in the case of an antagonist or inverse
agonist) under certain
conditions against one or more opioid receptor subtypes with respect to the
degree and/or
nature of activity against one or more other opioid receptor subtypes. For
example, in some
222
CA 02726300 2010-12-22
embodiments, the neurogenic agent has an antagonist effect against one or more
subtypes,
and a much weaker effect or substantially no effect against other subtypes. As
another
example, an additional neurogenic agent used in the methods described herein
may act as an
agonist at one or more opioid receptor subtypes and as antagonist at one or
more other opioid
receptor subtypes. In some embodiments, a neurogenic agent has activity
against kappa
opioid receptors, while having substantially lesser activity against one or
both of the delta and
mu receptor subtypes. In other embodiments, a neurogenic agent has activity
against two
opioid receptor subtypes, such as the kappa and delta subtypes. As non-
limiting examples,
the agents naloxone and naltrexone have nonselective antagonist activities
against more than
one opioid receptor subtypes. In certain embodiments, selective activity of
one or more
opioid antagonists results in enhanced efficacy, fewer side effects, lower
effective dosages,
less frequent dosing, or other desirable attributes.
[0466] An opioid receptor antagonist is an agent able to inhibit one or more
characteristic
responses of an opioid receptor or receptor subtype. As a non-limiting
example, an
antagonist may competitively or non-competitively bind to an opioid receptor,
an agonist or
partial agonist (or other ligand) of a receptor, and/or a downstream signaling
molecule to
inhibit a receptor's function.
[0467] An inverse agonist able to block or inhibit a constitutive activity of
an opioid
receptor may also be used. An inverse agonist may competitively or non-
competitively bind
to an opioid receptor and/or a downstream signaling molecule to inhibit a
receptor's function.
Non-limiting examples of inverse agonists for use in the disclosed methods
include ICI-
174864 (N,N-diallyl-Tyr-Aib-Aib-Phe-Leu), RTI-5989-1, RTI-5989-23, and RTI-
5989-25
(see Zaki et al. J. Pharmacol. Exp. Therap. 298(3): 1015-1020, 2001).
[0468] In other embodiments, the neurogenic agent in combination with a 5HTR
agent is a
reported GABA modulator which modulates GABA receptor activity at the receptor
level
(e.g., by binding directly to GABA receptors), at the transcriptional and/or
translational level
(e.g., by preventing GABA receptor gene expression), and/or by other modes
(e.g., by
binding to a ligand or effector of a GABA receptor, or by modulating the
activity of an agent
that directly or indirectly modulates GABA receptor activity). Non-limiting
examples of
GABA-A receptor modulators useful in methods described herein include
triazolophthalazine
derivatives, such as those disclosed in WO 99/25353, and WO/98/04560;
tricyclic pyrazolo-
pyridazinone analogues, such as those disclosed in WO 99/00391; fenamates,
such as those
223
CA 02726300 2010-12-22
disclosed in 5,637,617; triazolo-pyridazine derivatives, such as those
disclosed in WO
99/37649, WO 99/37648, and WO 99/37644; pyrazolo-pyridine derivatives, such as
those
disclosed in WO 99/48892; nicotinic derivatives, such as those disclosed in WO
99/43661
and 5,723,462; muscimol, thiomuscimol, and compounds disclosed in 3,242,190;
baclofen
and compounds disclosed in 3,471,548; phaclofen; quisqualamine; ZAPA;
zaleplon; THIP;
imidazole-4-acetic acid (IMA); (+)-bicuculline; gabalinoleamide; isoguvicaine;
3-
aminopropane sulphonic acid; piperidine-4-sulphonic acid; 4,5,6,7-tetrahydro-
[5,4-c]-
pyridin-3-ol; SR 95531; RU5315; CGP 55845; CGP 35348; FG 8094; SCH 50911; NG2-
73;
NGD-96-3; pricrotoxin and other bicyclophosphates disclosed in Bowery et al.,
Br. J.
Pharmacol., 57; 435 (1976).
[04691 Additional non-limiting examples of GABA-A modulators include compounds
described in 6,503,925; 6,218,547; 6,399,604; 6,646,124; 6,515,140; 6,451,809;
6,448,259;
6,448,246; 6,423,711; 6,414,147; 6,399,604; 6,380,209; 6,353,109; 6,297,256;
6,297,252;
6,268,496; 6,211,365; 6,166,203; 6,177,569; 6,194,427; 6,156,898; 6,143,760;
6,127,395;
6,103,903; 6,103,731; 6,723,735; 6,479,506; 6,476,030; 6,337,331; 6,730,676;
6,730,681;
6,828,322; 6,872,720; 6,699,859; 6,696,444; 6,617,326; 6,608,062; 6,579,875;
6,541,484;
6,500,828; 6,355,798; 6,333,336; 6,319,924; 6,303,605; 6,303,597; 6,291,460;
6,255,305;
6,133,255; 6,872,731; 6,900,215; 6,642,229; 6,593,325; 6,914,060; 6,914,063;
6,914,065;
6,936,608; 6,534,505; 6,426,343; 6,313,125 ; 6,310,203; 6,200,975; 6,071,909;
5,922,724;
6,096,887; 6,080,873; 6,013,799; 5,936,095; 5,925,770; 5,910,590; 5,908,932;
5,849,927;
5,840,888; 5,817,813; 5,804,686; 5,792,766; 5,750,702; 5,744,603; 5,744,602;
5,723,462;
5,696,260; 5,693,801; 5,677,309; 5,668,283; 5,637,725; 5,637,724; 5,625,063;
5,610,299;
5,608,079; 5,606,059; 5,604,235; 5,585,490; 5,510,480; 5,484,944; 5,473,073;
5,463,054;
5,451,585; 5,426,186; 5,367,077; 5,328,912 5,326,868; 5,312,822; 5,306,819;
5,286,860;
5,266,698; 5,243,049; 5,216,159; 5,212,310; 5,185,446; 5,185,446; 5,182,290;
5,130,430;
5,095,015; 20050014939; 20040171633; 20050165048; 20050165023; 20040259818;
and
20040192692.
104701 In some embodiments, the GABA-A modulator is a subunit-selective
modulator.
Non-limiting examples of GABA-A modulator having specificity for the alphal
subunit
include alpidem and zolpidem. Non-limiting examples of GABA-A modulator having
specificity for the alpha2 and/or alpha3 subunits include compounds described
in 6,730,681;
6,828,322; 6,872,720; 6,699,859; 6,696,444; 6,617,326; 6,608,062; 6,579,875;
6,541,484;
224
CA 02726300 2010-12-22
6,500,828; 6,355,798; 6,333,336; 6,319,924; 6,303,605; 6,303,597; 6,291,460;
6,255,305;
6,133,255; 6,900,215; 6,642,229; 6,593,325; and 6,914,063. Non-limiting
examples of
GABA-A modulator having specificity for the alpha2, alpha3 and/or alphas
subunits include
compounds described in 6,730,676 and 6,936,608. Non-limiting examples of GABA-
A
modulators having specificity for the alphas subunit include compounds
described in
6,534,505; 6,426,343; 6,313,125 ; 6,310,203; 6,200,975 and 6,399,604.
Additional non-
limiting subunit selective GABA-A modulators include CL218,872 and related
compounds
disclosed in Squires et al., Pharmacol. Biochem. Behav., 10: 825 (1979); and
beta-carboline-
3-carboxylic acid esters described in Nielsen et al., Nature, 286: 606 (1980).
104711 In some embodiments, the GABA-A receptor modulator is a reported
allosteric
modulator. In various embodiments, allosteric modulators modulate one or more
aspects of
the activity of GABA at the target GABA receptor, such as potency, maximal
effect, affinity,
and/or responsiveness to other GABA modulators. In some embodiments,
allosteric
modulators potentiate the effect of GABA (e.g., positive allosteric
modulators), and/or reduce
the effect of GABA (e.g., inverse agonists). Non-limiting examples of
benzodiazepine
GABA-A modulators include aiprazolam, bentazepam, bretazenil, bromazepam,
brotizolam,
cannazepam, chlordiazepoxide, clobazam, clonazepam, cinolazepam, clotiazepam,
cloxazolam, clozapin, delorazepam, diazepam, dibenzepin, dipotassium
chlorazepat,
divaplon, estazolam, ethyl-loflazepat, etizolam, fludiazepam, flumazenil,
flunitrazepam,
flurazepam 1 HC1, flutoprazepam, halazeparn, haloxazolam, imidazenil,
ketazolam,
lorazepam, loprazolam, lormetazepam, medazepam, metaclazepam, mexozolam,
midazolam-
HCI, nabanezil, nimetazepam, nitrazepam, nordazepam, oxazepam-tazepam,
oxazolam,
pinazepam, prazepam, quazepam, sarmazenil, suriclone, temazepam, tetrazepam,
tofisopam,
triazolam, zaleplon, zolezepam, zolpidem, zopiclone, and zopielon.
[04721 Additional non-limiting examples of benzodiazepine GABA-A modulators
include
Ro15-4513, CL218872, CGS 8216, CGS 9895, PK 9084, U-93631, beta-CCM, beta-CCB,
beta-CCP, Ro 19-8022, CGS 20625, NNC 14-0590, Ru 33-203, 5-amino-l-
bromouracil,
GYKI-52322, FG 8205, Ro 19-4603, ZG-63, RWJ46771, SX-3228, and L-655,078; NNC
14-
0578, NNC 14-8198, and additional compounds described in Wong et al., Eur J
Pharmacol
209: 319-325 (1995); Y-23684 and additional compounds in Yasumatsu et al., Br
J
Pharmacol 111: 1170-1178 (1994); and compounds described in U.S. Patent
4,513,135.
225
CA 02726300 2010-12-22
[04731 Non-limiting examples of barbiturate or barbituric acid derivative GABA-
A
modulators include phenobarbital, pentobarbital, pentobarbitone, primidone,
barbexaclon,
dipropyl barbituric acid, eunarcon, hexobarbital, mephobarbital, methohexital,
Na-
methohexital, 2,4,6(1H,3H,5)-pyrimidintrion, seebutabarbital and/or
thiopental.
[04741 Non-limiting examples of neurosteroid GABA-A modulators include
alphaxalone,
allotetrahydrodeoxycorticosterone, tetrahydrodeoxycorticosterone, estrogen,
progesterone 3-
beta-hydroxyandrost-5-en-17-on-3-sulfate, dehydroepianrosterone, eltanolone,
ethinylestradiol, 5-pregnen-3-beta-ol-20 on-sulfate, 5a-pregnan-3a-ol-20-one
(5PG),
allopregnanolone, pregnanolone, and steroid derivatives and metabolites
described in
5,939,545, 5,925,630, 6,277,838, 6,143,736, RE35,517, 5,925,630, 5,591,733,
5,232,917,
20050176976, WO 96116076, WO 98/05337, WO 95/21617, WO 94/27608, WO 93/18053,
WO 93/05786, WO 93/03732,, WO 91116897, EP01038880, and Han et al., J. Med.
Chem.,
36, 3956-3967 (1993), Anderson et al., J. Med. Chem., 40, 1668-1681 (1997),
Hogenkamp et
al., J. Med. Chem., 40, 61-72 (1997), Upasani et al., J. Med. Chem., 40, 73-84
(1997),
Majewska et al., Science 232:1004-1007 (1986), Harrison et al., J. Pharmacol.
Exp. Ther.
241:346-353 (1987), Gee et al., Eur. J. Pharmacol., 136:419-423 (1987) and
Birtran et al.,
Brain Res., 561, 157-161 (1991).
[04751 Non-limiting examples of beta-carboline GABA-A modulators include
abecarnil,
3,4-dihydro-beta-carboline, gedocarnil, 1-methyl-l-vinyl-2,3,4-trihydro-beta-
carboline-3-
carboxylic acid, 6-methoxy-1,2,3,4-tetrahydro-beta-carboline, N-BOC-L-1,2,3,4-
tetrahydro-
beta-carboline-3-carboxylic acid, tryptoline, pinoline, methoxyharmalan,
tetrahydro-beta-
carboline (THBC), 1-methyl-THBC, 6-methoxy-THBC, 6-hydroxy-THBC, 6-
methoxyharmalan, norharman, 3,4-dihydro-beta-carboline, and compounds
described in
Nielsen et al., Nature, 286: 606 (1980).
[04761 In some embodiments, the GABA modulator modulates GABA-B receptor
activity. Non-limiting examples of reported GABA-B receptor modulators useful
in methods
described herein include CGP36742; CGP-64213; CGP 56999A; CGP 54433A; CGP
36742;
SCH 50911; CGP 7930; CGP 13501; baclofen and compounds disclosed in 3,471,548;
saclofen; phaclofen; 2-hydroxysaclofen; SKF 97541; CGP 35348 and related
compounds
described in Olpe, et al, Eur. J. Pharmacol., 187, 27 (1990); phosphinic acid
derivatives
described in Hills, et al, Br. J. Pharmacol., 102, pp. 5-6 (1991); and
compounds described in
4,656,298, 5,929,236, EP0463969, EP 0356128, Kaupmann et al., Nature 368: 239
(1997),
226
CA 02726300 2010-12-22
Karla et al., J Med Chem., 42(11):2053-9 (1992), Ansar et al., Therapie,
54(5):651-8 (1999),
and Castelli et al., Eur J Pharmacol., 446(1-3):1-5 (2002).
[0477] In some embodiments, the GABA modulator modulates GABA-C receptor
activity. Non-limiting examples of reported GABA-C receptor modulators useful
in methods
described herein include cis-aminocrotonic acid (CACA); 1,2,5,6-
tetrahydropyridine-4-yl
methyl phosphinic acid (TPMPA) and related compounds such as P4MPA, PPA and
SEPI; 2-
methyl-TACA; (+/-)-TAMP; muscimol and compounds disclosed in 3,242,190; ZAPA;
THIP
and related analogues, such as aza-THIP; pricotroxin; imidazole-4-acetic acid
(IMA); and
CGP36742.
[0478] In some embodiments, the GABA modulator modulates the activity of
glutamic
acid decarboxylase (GAD).
[0479] In some embodiments, the GABA modulator modulates GABA transaminase
(GTA). Non-limiting examples of GTA modulators include the GABA analog
vigabatrin,
and compounds disclosed in 3,960,927.
[0480] In some embodiments, the GABA modulator modulates the reuptake and/or
transport of GABA from extracellular regions. In other embodiments, the GABA
modulator
modulates the activity of the GABA transporters, GAT-1, GAT-2, GAT-3 and/or
BGT-1.
Non-limiting examples of GABA reuptake and/or transport modulators include
nipecotic acid
and related derivatives, such as Cl 966; SKF 89976A; TACA; stiripentol;
tiagabine and
GAT-1 inhibitors disclosed in 5,010,090; (R)-l-(4,4-diphenyl-3-butenyl)-3-
piperidinecarboxylic acid and related compounds disclosed in 4,383,999; (R)-1-
[4,4-bis(3-
methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylic acid and related compounds
disclosed in
Anderson et al., J. Med. Chem. 36, (1993) 1716-1725; guvacine and related
compounds
disclosed in Krogsgaard-Larsen, Molecular & Cellular Biochemistry 31, 105-121
(1980);
GAT-4 inhibitors disclosed in 6,071,932; and compounds disclosed in 6,906,177
and Ali, F.
E., et al. J. Med. Chem. 1985, 28, 653-660. Methods for detecting GABA
reuptake inhibitors
are known in the art, and are described, e.g., in 6,906,177; 6,225,115;
4,383,999; Ali, F. E., et
al. J. Med. Chem. 1985, 28, 653-660.
[0481] In some embodiments, the GABA modulator is the benzodiazepine
clonazepam,
which is described, e.g., in 3,121,076 and 3,116,203; the benzodiazepine
diazepam, which is
described, e.g., in 3,371,085; 3,109,843; and 3,136,815; the short-acting
diazepam derivative
227
CA 02726300 2010-12-22
midazolam, which is a described, e.g., in 4,280,957; the imidazodiazepine
flumazenil, which
is described, e.g., in 4,316,839; the benzodiazepine lorazepam is described,
e.g., in 3,296,249;
the benzodiazepine L-655708, which is described, e.g., in Quirk et al.
Neuropharmacology
1996, 35, 1331; Sur et al. Mol. Pharmacol. 1998, 54, 928; and Sur et al. Brain
Res. 1999, 822,
265; the benzodiazepine gabitril; zopiclone, which binds the benzodiazepine
site on GABA-A
receptors, and is disclosed, e.g., in 3,862,149 and 4,220,646.; the GABA-A
potentiator
indiplon as described, e.g., in Foster et al., J Pharmacol Exp Ther.,
311(2):547-59 (2004),
4,521,422 and 4,900,836; zolpidem, described, e.g., in 4,794,185 and EP50563;
zaleplon,
described, e.g., in 4,626,538; abecamil, described, e.g., in Stephens et al.,
J Pharmacol Exp
Ther. , 253(1):334-43 (1990); the GABA-A agonist isoguvacine, which is
described, e.g., in
Chebib et al., Clin. Exp. Pharmacol. Physiol. 1999, 26, 937-940; Leinekugel et
al. J. Physiol.
1995, 487, 319-29; and White et al., J. Neurochem. 1983, 40(6), 1701-8; the
GABA-A
agonist gaboxadol (THIP), which is described, e.g., in 4,278,676 and
Krogsgaard-Larsen,
Acta. Chem. Scand. 1977, 31, 584; the GABA-A agonist muscimol, which is
described, e.g.,
in 3,242,190 and 3,397,209; the inverse GABA-A agonist beta-CCP, which is
described, e.g.,
in Nielsen et al., J. Neurochem., 36(1):276-85 (1981); the GABA-A potentiator
riluzole,
which is described, e.g., in 4,370,338 and EP 50,551; the GABA-B agonist and
GABA-C
antagonist SKF 97541, which is described, e.g., in Froestl et al., J.Med.Chem.
38 3297
(1995); Hoskison et al., Neurosci. Lett. 2004, 365(1), 48-53 and Hue et al.,
J. Insect Physiol.
1997, 43(12), 1125-1131; the GABA-B agonist baclofen, which is described,
e.g., in U.S.
Patent 3,471,548; the GABA-C agonist cis-4-aminocrotonic acid (CACA), which is
described, e. g., in Ulloor et al. J. Neurophysiol. 2004, 91(4), 1822-31; the
GABA-A
antagonist phaclofen, which is described, e.g., in Kerr et al. Brain Res.
1987, 405, 150;
Karlsson et al. Eur. J Pharmacol. 1988, 148, 485; and Hasuo, Gallagher
Neurosci. Lett. 1988,
86, 77; the GABA-A antagonist SR 95531, which is described, e.g., in Stell et
al. J. Neurosci.
2002, 22(10), RC223; Wermuth et al., J.Med.Chem. 30 239 (1987); and Luddens
and Korpi,
J.Neurosci. 15: 6957 (1995); the GABA-A antagonist bicuculline, which is a
described, e.g.,
in Groenewoud, J. Chem. Soc. 1936, 199; Olsen et al., Brain Res. 102: 283
(1976) and
Haworth et al. Nature 1950, 165, 529; the selective GABA-B antagonist CGP
35348, which
is described, e.g., in Olpe et al. Eur. J. Pharmacol. 1990, 187, 27; Hao et
al. Neurosci. Lett.
1994, 182, 299; and Froestl et al. Pharmacol. Rev. Comm. 1996, 8, 127; the
selective GABA-
B antagonist CGP 46381, which is described, e.g., in Lingenhoehl, Pharmacol.
Comm. 1993,
3, 49; the selective GABA-B antagonist CGP 52432, which is described, e.g., in
Lanza et al.
Eur. J. Pharmacol. 1993, 237, 191; Froestl et al. Pharmacol. Rev. Comm. 1996,
8, 127;
228
CA 02726300 2010-12-22
Bonanno et al. Eur. J. Pharmacol. 1998, 362, 143; and Libri et al. Naunyn-
Schmied. Arch.
Pharmacol. 1998, 358, 168; the selective GABA-B antagonist CGP 54626, which is
described, e.g., in Brugger et al. Eur. J. Pharmacol. 1993, 235, 153; Froestl
et al. Pharmacol.
Rev. Comm. 1996, 8, 127; and Kaupmann et al. Nature 1998, 396, 683; the
selective GABA-
B antagonist CGP 55845, which is a GABA-receptor antagonist described, e.g.,
in Davies et
al. Neuropharmacology 1993, 32, 1071; Froestl et al. Pharmacol. Rev. Comm.
1996, 8, 127;
and Deisz Neuroscience 1999, 93, 1241; the selective GABA-B antagonist
Saclofen, which is
described, e.g., in Bowery, TiPS, 1989, 10, 401; and Kerr et al. Neurosci
Lett. 1988;92(1):92-
6; the GABA-B antagonist 2-hydroxysaclofen, which is described, e.g., in Kerr
et al.
Neurosci. Lett. 1988, 92, 92; and Curtis et al. Neurosci. Lett. 1988, 92, 97;
the GABA-B
antagonist SCH 50,911, which is described, e.g., in Carruthers et al., Bioorg
Med Chem Lett
8: 3059-3064 (1998); Bolser et al. J. Pharmacol. Exp. Ther. 1996, 274, 1393;
Hosford et al.
J. Pharmacol. Exp. Ther. 1996, 274, 1399; and Ong et al. Eur. J. Pharmacol.
1998, 362, 35;
the selective GABA-C antagonist TPMPA, which is described, e.g., in Schlicker
et al., Brain
Res. Bull. 2004, 63(2), 91-7; Murata et al., Bioorg.Med.Chem.Lett. 6: 2073
(1996); and
Ragozzino et al., Mol.Pharmacol. 50: 1024 (1996); a GABA derivative, such as
Pregabalin
[(S)-(+)-3-isobutylgaba] or gabapentin [1-(aminomethyl)cyclohexane acetic
acid].
Gabapentin is described, e.g., in U.S. Patent 4,024,175; the lipid-soluble
GABA agonist
progabide, which is metabolized in vivo into GABA and/or pharmaceutically
active GABA
derivatives in vivo. Progabide is described, e.g., in U.S. Patents 4,094,992
and 4,361,583; the
GAT1 inhibitor Tiagabine, which is described, e.g., in U.S. Patent 5,010,090
and Andersen et
al. J. Med. Chem. 1993, 36, 1716; the GABA transaminase inhibitor valproic
acid (2-
propylpentanoic acid or dispropylacetic acid), which is described, e.g., in
U.S. Patent
4,699,927 and Carraz et al., Therapie, 1965, 20, 419; the GABA transaminase
inhibitor
vigabatrin, which is described, e.g., in U.S. Patent 3,960,927; or topiramate,
which is
described, e.g., in U.S. Patent 4,513,006.
[0482] In further embodiments, the neurogenic sensitizing agent may be a
reported direct
or indirect modulator of dopamine receptors. Non-limiting examples of such
agents include
the indirect dopamine agonists methylphenidate (CAS RN 113-45-1) or
methylphenidate
hydrochloride (also known as Ritalin CAS RN 298-59-9), amphetamine (CAS RN
300-62-
9) and methamphetamine (CAS RN 537-46-2), and the direct dopamine agonists
sumanirole
(CAS RN 179386-43-7), roprinirole (CAS RN 91374-21-9), and rotigotine (CAS RN
99755-
229
CA 02726300 2010-12-22
59-6). Additional non-limiting examples include 7-OH-DPAT, quinpirole,
haloperidole, or
clozapine.
[04831 Additional non-limiting examples include bromocriptine (CAS RN 25614-03-
3),
adrogolide (CAS RN 171752-56-0), pramipexole (CAS RN 104632-26-0), ropinirole
(CAS
RN 91374-21-9), apomorphine (CAS RN 58-00-4) or apomorphine hydrochloride (CAS
RN
314-19-2), lisuride (CAS RN 18016-80-3), sibenadet hydrochloride or viozan
(CAS RN
154189-24-9), L-DOPA or levodopa (CAS RN 59-92-7), melevodopa (CAS RN 7101-51-
1),
etilevodopa (CAS RN 37178-37-3), talipexole hydrochloride (CAS RN 36085-73-1)
or
talipexole (CAS RN 101626-70-4), nolomirole (CAS RN 90060-42-7), quinelorane
(CAS RN
97466-90-5), pergolide (CAS RN 66104-22-1), fenoldopam (CAS RN 67227-56-9),
carmoxirole (CAS RN 98323-83-2), terguride (CAS RN 37686-84-3), cabergoline
(CAS RN
81409-90-7), quinagolide (CAS RN 87056-78-8) or quinagolide hydrochloride (CAS
RN
94424-50-7), sumanirole, docarpamine (CAS RN 74639-40-0), SLV-308 or 2(3H)-
benzoxazolone, 7-(4-methyl-l-piperazinyl)-monohydrochloride (CAS RN 269718-83-
4),
aripiprazole (CAS RN 129722-12-9), bifeprunox, lisdexamfetamine dimesylate
(CAS RN
608137-33-3), safinamide (CAS RN 133865-89-1), or adderall or amfetamine (CAS
RN 300-
62-9).
[04841 In other embodiments, the neurogenic agent used in combination with a
5HTR
agent may be a reported modulator of a melatonin receptor. Non-limiting
examples of such
modulators include the melatonin receptor agonists melatonin, LY-156735 (CAS
RN
118702-11-7), agomelatine (CAS RN 138112-76-2), 6-chloromelatonin (CAS RN
63762-74-
3), ramelteon (CAS RN 196597-26-9), 2-Methyl-6,7-dichloromelatonin (CAS RN
104513-
29-3), and ML 23 (CAS RN 108929-03-9).
[04851 In embodiments relating to a biogenic amine modulator used in a
combination or
method with a 5HTR agent as disclosed herein, the modulator may be (i) a
norepinephrine
and dopamine reuptake inhibitor, such as bupropion (described, e.g., in U.S.
Pat. 3,819,706
and 3,885,046), or (S,S)-hydroxybupropion (described, e.g., in U.S. Pat.
6,342,496); (ii)
selective dopamine reuptake inhibitors, such as medifoxamine, amineptine
(described, e.g., in
U.S. Pat. 3,758,528 and 3,821,249), GBR12909, GBR12783 and GBR13069, described
in
Andersen, Eur J Pharmacol, 166:493-504 (1989); or (iii) a monoamine "releaser"
which
stimulates the release of monoamines, such as biogenic amines from presynaptic
sites, e.g.,
by modulating presynaptic receptors (e.g., autoreceptors, heteroreceptors),
modulating the
230
CA 02726300 2010-12-22
packaging (e.g., vesicular formation) and/or release (e.g., vesicular fusion
and release) of
monoamines, and/or otherwise modulating monoamine release. Advantageously,
monoamine
releasers provide a method for increasing levels of one or more monoamines
within the
synaptic cleft or other extracellular region independently of the activity of
the presynaptic
neuron.
[04861 In additional embodiments, an agent in combination with a 5HTR agent
may be a
component of a natural product or a derivative of such a component. In some
embodiments,
the component or derivative thereof is in an isolated form, such as that which
is separated
from one or more molecules or macromolecules normally found with the component
or
derivative before use in a combination or method as disclosed herein. In other
embodiments,
the component or derivative is completely or partially purified from one or
more molecules or
macromolecules normally found with the component or derivative. Exemplary
cases of
molecules or macromolecules found with a component or derivative as described
herein
include a plant or plant part, an animal or animal part, and a food or
beverage product.
104871 Non-limiting examples such a component include folic acid; a flavinoid,
such as a
citrus flavonoid; a flavonol, such as quercetin, kaempferol, myricetin, or
isorhamnetin; a
flavone, such as luteolin or apigenin; a flavanone, such as hesperetin,
naringenin, or
eriodictyol; a flavan-3-ol (including a monomeric, dimeric, or polymeric
flavanol), such as
(+)-catechin, (+)-gallocatechin, (-)-epicatechin, (-)-epigallocatechin, (-)-
epicatechin 3-gallate,
(-)-epigallocatechin 3-gallate, theaflavin, theaflavin 3-gallate, theaflavin
3'-gallate, theaflavin
3,3' digallate, a thearubigin, or proanthocyanidin; an anthocyanidin, such as
cyanidin,
delphinidin, malvidin, pelargonidin, peonidin, or petunidin; an isoflavone,
such as daidzein,
genistein, or glycitein; flavopiridol; a prenylated chalcone, such as
xanthohumol; a prenylated
flavanone, such as isoxanthohumol; a non-prenylated chalcone, such as
chalconaringenin; a
non-prenylated flavanone, such as naringenin; resveratrol; or an anti-oxidant
neutraceutical
(such as any present in chocolate, like dark chocolate or unprocessed or
unrefined chocolate).
104881 Additional non-limiting examples include a component of Gingko biloba,
such as a
flavo glycoside or a terpene. In some embodiments, the component is a
flavanoid, such as a
flavonol or flavone glycoside, or a quercetin or kaempferol glycoside, or
rutin; or a terpenoid,
such as ginkgolides A, B, C, or M, or bilobalide.
231
CA 02726300 2010-12-22
[0489] Further non-limiting examples include a component that is a flavanol,
or a related
oligomer, or a polyphenol as described in US2005/245601AA, US2002/018807AA,
US2003/180406AA, US2002/086833AA, US2004/0236123, W09809533, or W09945788; a
procyanidin or derivative thereof or polyphenol as described in
US2005/171029AA; a
procyanidin, optionally in combination with L-arginine as described in
US2003/104075AA; a
low fat cocoa extract as described in US2005/031762AA; lipophilic bioactive
compound
containing composition as described in US2002/107292AA; a cocoa extract, such
as those
containing one or more polyphenols or procyanidins as described in
US2002/004523AA; an
extract of oxidized tea leaves as described in US Pat. 5,139,802 or 5,130,154;
a food
supplement as described in WO 2002/024002.
[0490] Of course a composition comprising any of the above components, alone
or in
combination with a 5HTR agent as described herein is included within the
disclosure.
[0491] In additional embodiments, an agent in combination with a 5HTR agent
may be a
reported modulator of a norepinephrine receptor. Non-limiting examples include
atomoxetine (Strattera ); a norepinephrine reuptake inhibitor, such as
talsupram, tomoxetine,
nortriptyline, nisoxetine, reboxetine (described, e.g., in U.S. Pat.
4,229,449), or tomoxetine
(described, e.g., in U.S. Pat. 4,314,081); or a direct agonist, such as a beta
adrenergic agonist.
[0492] Additional non-limiting examples include an alpha adrenergic agonist
such as
etilefrine or a reported agonist of the a2-adrenergic receptor (or a2
adrenoceptor) like
clonidine (CAS RN 4205-90-7), yohimbine, mirtazepine, atipamezole, carvedilol;
dexmedetomidine or dexmedetomidine hydrochloride; ephedrine, epinephrine;
etilefrine;
lidamidine; tetramethylpyrazine; tizanidine or tizanidine hydrochloride;
apraclonidine;
bitolterol mesylate; brimonidine or brimonidine tartrate; dipivefrin (which is
converted to
epinephrine in vivo); guanabenz; guanfacine; methyldopa;
alphamethylnoradrenaline;
mivazerol; natural ephedrine or D(-)ephedrine; any one or any mixture of two,
three, or four
of the optically active forms of ephedrine; CHF1035 or nolomirole
hydrochloride (CAS RN
138531-51-8); or lofexidine (CAS RN 31036-80-3).
[0493] Alternative non-limiting examples include an adrenergic antagonist such
as a
reported antagonist of the a2-adrenergic receptor like yohimbine (CAS RN 146-
48-5) or
yohimbine hydrochloride, idazoxan, fluparoxan, mirtazepine, atipamezole, or
RX781094 (see
232
CA 02726300 2010-12-22
Elliott et al. "Peripheral pre and postjunctional alpha 2-adrenoceptors in
man: studies with
RX781094, a selective alpha 2 antagonist." J Hypertens Suppl. 1983 1(2):109-
11).
[0494] Other non-limiting embodiments include a reported modulator of an a 1-
adrenergic
receptor such as cirazoline; modafinil; armodafinil; ergotamine; metaraminol;
methoxamine;
midodrine (a prodrug which is metabolized to the major metabolite
desglymidodrine formed
by deglycination of midodrine); oxymetazoline; phenylephrine;
phenylpropanolamine; or
pseudoephedrine.
[0495] Further non-limiting embodiments include a reported modulator of a beta
adrenergic receptor such as arbutamine, befunolol, cimaterol, higenamine,
isoxsuprine,
methoxyphenamine, oxyfedrine, ractopamine, tretoquinol, or TQ-1016 (from
TheraQuest
Biosciences, LLC), or a reported 0 1-adrenergic receptor modulator such as
prenalterol, Ro
363, or xamoterol or a reported [31-adrenergic receptor agonist like
dobutamine.
[0496] Alternatively, the reported modulator may be of a (32-adrenergic
receptor such as
levosalbutamol (CAS RN 34391-04-3), metaproterenol, MN-221 or KUR-1246 ((-)-
bis(2-
{[(2S)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(2-hydroxyethyl) phenyl] ethyl)
amino)- 1,2,3,4-
tetrahydronaphthalen-7-ylloxyl-N,N-dimethylacetamide)monosulfate or bis(2-
[[(2S)-2-
([(2R)-2-hydroxy-2-[4-hydroxy-3 -(2-hydroxyethyl)-phenyl] ethyl] amino)-
1,2,3,4-
tetrahydronaphthalen-7-yl]oxy]-N,N-dimethylacetamide) sulfate or CAS RN 194785-
31-4),
nylidrin, orciprenaline, pirbuterol, procaterol, reproterol, ritodrine,
salmeterol, salmeterol
xinafoate, terbutaline, tulobuterol, zinterol or
bromoacetylalprenololmenthane, or a reported
^-adrenergic receptor agonist like albuterol, albuterol sulfate, salbutamol
(CAS RN 35763-
26-9), clenbuterol, broxaterol, dopexamine, formoterol, formoterol fumarate,
isoetharine,
levalbuterol tartrate hydrofluoroalkane, or mabuterol.
[0497] Additional non-limiting embodiments include a reported modulator of a
133-
adrenergic receptor such as AJ-9677 or TAK677 ([3-[(2R)-[{(2R)-(3-
chlorophenyl)-2-
hydroxyethyl]amino]propyl]-1H-indol-7-yloxy]acetic acid), or a reported (33-
adrenergic
receptor agonist like SR58611A (described in Simiand et al., Eur J Pharmacol,
219:193-201
(1992), BRL 26830A, BRL 35135, BRL 37344, CL 316243 or ICI D7114.
[0498] Further alternative embodiments include a reported nonselective alpha
and beta
adrenergic receptor agonist such as epinephrine or ephedrine; a reported
nonselective alpha
and beta adrenergic receptor antagonist such as carvedilol; a [31 and f32
adrenergic receptor
233
CA 02726300 2010-12-22
agonist such as isopreoterenol; or a 01 and 02 adrenergic receptor antagonist
such as CGP
12177, fenoterol, or hexoprenaline.
[0499] Non-limiting examples of reported adrenergic agonists include
albuterol, albuterol
sulfate, salbutamol (CAS RN 35763-26-9), clenbuterol, adrafinil, and SR58611A
(described
in Simiand et al., Eur J Pharmacol, 219:193-201 (1992)), clonidine (CAS RN
4205-90-7),
yohimbine (CAS RN 146-48-5) or yohimbine hydrochloride, arbutamine;
armodafinil;
befunolol; BRL 26830A; BRL 35135; BRL 37344; bromoacetylalprenololmenthane;
broxaterol; carvedilol; CGP 12177; cimaterol; cirazoline; CL 316243;
clenbuterol;
denopamine; dexmedetomidine or dexmedetomidine hydrochloride; dobutamine,
dopexamine, ephedrine, epinephrine, etilefrine; fenoterol; formoterol;
formoterol fumarate;
hexoprenaline; higenamine; ICI D7114; isoetharine; isoproterenol; isoxsuprine;
levalbuterol
tartrate hydrofluoroalkane; lidamidine; mabuterol; methoxyphenamine;
modafinil; nylidrin;
orciprenaline; oxyfedrine; pirbuterol; prenalterol; procaterol; ractopamine;
reproterol;
ritodrine; ro 363; salmeterol; salmeterol xinafoate; terbutaline;
tetramethylpyrazine;
tizanidine or tizanidine hydrochloride; tretoquinol; tulobuterol; xamoterol;
or zinterol.
Additional non-limiting examples include apraclonidine, bitolterol mesylate,
brimonidine or
brimonidine tartrate, dipivefrin (which is converted to epinephrine in vivo),
epinephrine,
ergotamine, guanabenz, guanfacine, metaproterenol, metaraminol, methoxamine,
methyldopa, midodrine (a prodrug which is metabolized to the major metabolite
desglymidodrine formed by deglycination of midodrine), oxymetazoline,
phenylephrine,
phenylpropanolamine, pseudoephedrine, alphamethylnoradrenaline, mivazerol,
natural
ephedrine or D(-)ephedrine, any one or any mixture of two, three, or four of
the optically
active forms of ephedrine, CHF1035 or nolomirole hydrochloride (CAS RN 138531-
51-8),
AJ-9677 or TAK677 ([3-[(2R)-[[(2R)-(3-chlorophenyl)-2-
hydroxyethyl]amino]propyl]-IH-
indol-7-yloxy] acetic acid), MN-221 or KUR-1246 ((-)-bis(2-{[(2S)-2-({(2R)-2-
hydroxy-2-[4-
hydroxy-3-(2-hydroxyethyl) phenyl] ethyl}amino)-1,2,3,4-tetrahydronaphthalen-7-
yl]oxy}-
N,N-dimethylacetamide)monosulfate or bis(2-[[(2S)-2-([(2R)-2-hydroxy-2-[4-
hydroxy-3-(2-
hydroxyethyl )-phenyl] ethyl] amino)-1,2,3,4-tetrahydronaphthalen-7-yl] oxy] -
N,N-
dimethylacetamide) sulfate or CAS RN 194785-31-4), levosalbutamol (CAS RN
34391-04-
3), lofexidine (CAS RN 31036-80-3) or TQ-1016 (from TheraQuest Biosciences,
LLC).
234
CA 02726300 2010-12-22
[0500] In further embodiments, a reported adrenergic antagonist, such as
idazoxan or
fluparoxan, may be used as an agent in combination with a nootropic agent as
described
herein.
[0501] Having now generally described the invention, the same will be more
readily
understood through reference to the following examples which are provided by
way of
illustration, and are not intended to be limiting of the disclosed invention,
unless specified.
EXAMPLES
EXAMPLE 1
EFFECT ON NEURONAL
DIFFERENTIATION OF HUMAN NEURAL STEM CELLS
[0502] Human neural stem cells (hNSCs) were isolated and grown in monolayer
culture,
plated, treated with varying concentrations of 5-HTP (test compound), and
stained with TUJ-
I antibody, as described in PCT Application No. US06/026677 (hereby
incorporated by
reference as if fully set forth). Mitogen-free test media with a positive
control was used for
neuronal differentiation, and basal media without growth factors served as a
negative control.
[0503] Results are shown in Figure 1, which shows dose response curves of
neuronal
differentiation after background media values are subtracted. The dose
response curve of the
neuronal positive control is included as a reference. The data is presented as
a percent of
neuronal positive control. The data indicate that 5-HTP weakly promoted
neuronal
differentiation.
EXAMPLE 2
EFFECT ON ASTROCYTE DIFFERENTIATION OF hNSCs
[0504] Experiments were carried out as described in Example 1, except the
positive
control for astrocyte differentiation contained mitogen-free test media with a
positive control,
and cells were stained with GFAP antibody. Results are shown in Figure 2,
which shows
dose response curves of astrocyte differentiation after background media
values are
subtracted. 5-HTP showed no significant increase in astrocyte differentiation
above basal
media values.
235
CA 02726300 2010-12-22
EXAMPLE 3
IMMUNOHISTOCHEMISTRY WITH NEURONAL
AND ASTROCYTE MARKERS
[05051 Immunohistochemistry was carried out as described above using TUJ-1 as
a
neuronal cell marker and GFAP as an astrocyte marker. The results are shown in
Figure 3,
with control images included at the top for reference, and cells treated with
10.0 M 5-HTP
shown at the bottom.
EXAMPLE 4
EFFECT OF 5-HT1a AGONISTS ON NEURONAL
DIFFERENTIATION OF HUMAN NEURAL STEM CELLS
[05061 Human neural stem cells (hNSCs) were isolated and grown in monolayer
culture,
plated, treated with varying concentrations of test compounds, and stained
with TUJ-1
antibody, as described in Example 1. Mitogen-free test media with a positive
control for
neuronal differentiation was used, and basal media without growth factors
served as a
negative control.
[05071 Results are shown for the 5-HT 1 a agonist buspirone in Figure 4 and
for the 5-
HTI a agonist tandospirone in Figure 7, which show dose response curves of
neuronal
differentiation after background media values are subtracted. The dose
response curve of the
neuronal positive control is included as a reference. The data is presented as
a percent of
neuronal positive control. The data indicate that 5-HT1a agonists promoted
neuronal
differentiation.
EXAMPLE 5
EFFECT OF 5-HT1a AGONISTS ON
ASTROCYTE DIFFERENTIATION OF hNSCs
[05081 Experiments were carried out as described in Example 2, except the
positive
control for astrocyte differentiation contained mitogen-free test media with a
different
positive control. Results are shown for the 5-HTI a agonist buspirone in
Figure 5 and for the
5-HT 1 a agonist tandospirone in Figure 8, which show dose response curves of
astrocyte
differentiation after background media values are subtracted. The data
indicate that 5-HT1 a
agonists promoted astrocytic differentiation, compared to 5-HTP as described
in Example 2
and Figure 2.
236
CA 02726300 2010-12-22
EXAMPLE 6
IMMUNOHISTOCHEMISTRY WITH NEURONAL AND
ASTROCYTE MARKERS ON hNSCs TREATED WITH 5-HT1a AGONISTS
105091 Immunohistochemistry was carried out as described in Example 3. The
results are
shown for the 5-HT 1 a agonist buspirone in Figure 6 and for the 5-HT 1 a
agonist tandospirone
in Figure 9, with control images included at the top of each figure for
reference, and cells
treated with 31.6 gM test compound shown at the bottom of each figure.
EXAMPLE 7
EFFECT OF THE SSRI FLUOXETINE IN THE IN VIVO
NOVEL OBJECT RECOGNITION COGNITION ASSAY
[05101 Male F344 rats were dosed lx per day for 28-days with 0 (vehicle only)
or 5.0 and
10.0 mg/kg fluoxetine (n = 12 per dose group, p.o.). The apparatus consisted
of an open field
(45 x 45 x 50cm high) made of polycarbonate. Triplicate copies were used of
the objects to
be discriminated. Care was taken to ensure that the pair of objects tested
were made from the
same material so that they could not be distinguished readily by olfactory
cues although they
had very different appearances.
[05111 Each test session consisted of two phases. In the initial
familiarization phase, two
identical objects (Al and A2) were placed in the far corners of the box arena.
A rat was then
placed in the middle of the arena and allowed 15 minutes to explore both
objects.
Exploration of an object was defined as directing the nose to the object at a
distance of less
than 2 cm and/or touching it with the nose. After a delay of 48-hours the rat
was re-
introduced to the arena ("test phase"). The box now contained a third
identical copy of the
familiar object (A3) and a new object (B). These were placed in the same
locations as the
sample stimuli, whereby the position (left or right) of the novel object in
the test phase was
balanced between rats. For half the rats, object A was the sample and object B
was the novel
alternative. The test phase was 15 minutes in duration, with the first 30
seconds of object
interaction used to determine preference scores. Any animal with less than 15
seconds of
object exploration were excluded from analysis. Figure I OA shows the mean
preference
based on visits to the novel object. Figure I OB shows the mean preference
based on time
spent exploring the novel object. Fluoxetine produced a dose dependent
increase in
preference for the novel object suggesting cognitive enhancement with chronic
fluoxetine.
237
CA 02726300 2010-12-22
EXAMPLE 8
EFFECT OF THE SSRI FLUOXETINE IN THE IN VIVO
NOVELTY SUPPRESSED FEEDING DEPRESSION ASSAY
105121 Male F344 rats were dosed lx per day for 21-days with 0 (vehicle only)
or 10.0
mg/kg fluoxetine (n = 12 per dose group, p.o.). Twenty-four hours prior to
behavioral
testing, all food is removed from the home cage. At the time of testing a
single pellet is
placed in the center of a novel arena. Animals are placed in the corner of the
arena and
latency to eat the pellet is recorded. Compounds are generally administered 30
minutes prior
to testing. Animals receive compound daily for 21 days and testing is
performed on day 21.
A decreased latency to eat the food pellet is indicative of both neurogenesis
and
antidepressant activity. Figure 11 shows the mean latency to approach and eat
a food pellet
within the novel environment. Fluoxetine treatment reduced the latency to eat
the food pellet
indicating anti-depressant activity of chronic fluoxetine.
EXAMPLE 9
EFFECT OF THE 5-HT1a AGONIST BUSPIRONE IN THE IN VIVO
NOVEL OBJECT RECOGNITION COGNITION ASSAY
105131 Male F344 rats were dosed lx per day for 28-days with 0 (vehicle only)
or 0.5 and
5.0 mg/kg buspirone (n = 12 per dose group, i.p.). Behavioral testing was
carried out as
described in Example 7. The results are shown for the 5-HT1 a agonist
buspirone in Figure
12. Figure 12A shows the mean preference based on visits to the novel object.
Figure 12B
shows the mean preference based on time spent exploring the novel object.
Buspirone did
not increase preference for the novel object indicating an absence of
cognitive enhancement
with chronic buspirone.
EXAMPLE 10
EFFECT OF THE 5-HT1a AGONIST BUSPIRONE IN THE IN VIVO
NOVELTY SUPPRESSED FEEDING DEPRESSION ASSAY
[05141 Male F344 rats were dosed lx per day for 21-days with 0 (vehicle only)
or 0.5 and
5.0 mg/kg buspirone (n = 12 per dose group, i.p.). Behavioral testing was
carried out as
described in Example 8. Figure 13 shows the mean latency to approach and eat a
food pellet
within the novel environment. Buspirone treatment did not significantly reduce
the latency to
eat the food pellet indicating an absence of anti-depressant activity with
chronic buspirone.
238
CA 02726300 2010-12-22
EXAMPLE 11
EFFECT OF CHRONIC DOSING OF THE 5-HTla
AGONIST BUSPIRONE ON RAT BODY WEIGHT
[05151 Male F344 rats were dosed lx per day for 28-days with 0(vehicle only)
or 0.5 and
5.0 mg/kg buspirone (n = 12 per dose group, i.p.). Body weights were collected
daily.
Figure 14 shows the mean body weight over the 28-days of dosing. Buspirone
treatment led
to a gradual decrease in body weight relative to vehicle treated controls
starting after 7 days
of treatment and lasting throughout the length of the experiment.
EXAMPLE 12
EFFECT OF 5-HTP IN COMBINATION WITH AN ADDITIONAL
AGENT UPON DIFFERENTIATION OF HUMAN NEURAL STEM CELLS
105161 Experiments with various concentrations of 5-HTP with dopamine were
carried out
generally as described in Example 1 for neuronal differentiation. The results
are shown in
Figure 15, which shows dose response curves for neuronal differentiation after
background
media values are subtracted. Dopamine alone did not significantly enhance
neuronal
differentiation. The combination of 10 M or 30 M 5-HTP with the non-
neurogenic, but
sensitizing, agent dopamine enhanced the stimulation of neuronal
differentiation by
dopamine in a dose-dependent manner. These data demonstrate that the
combination of a
5HT1 a receptor agonist and a neurogenic sensitizing agent can significantly
enhance the
combined neurogenie effects of the agents.
EXAMPLE 13
EFFECTS OF THE 5-HT1a AGONIST BUSPIRONE IN COMBINATION
WITH THE MELATONIN AGONIST MELATONIN
ON DIFFERENTIATION OF HUMAN NEURAL STEM CELLS
105171 Human neural stem cells (hNSCs) were isolated and grown in monolayer
culture,
plated, treated with varying concentrations of buspirone in the presence or
absence of the
melatonin agonist melatonin, and stained with TUJ-1 antibody for the detection
of neuronal
differentiation or GFAP antibody for the detection of astrocyte
differentiation, as described
above. Mitogen-free test media with a positive control for neuronal
differentiation was used
along with basal media without growth factors as a negative control.
105181 Results are shown in Figures 17 and 18, which show concentration
response curves
of neuronal and astrocyte differentiation respectively, after background media
values are
239
CA 02726300 2010-12-22
subtracted. The concentration response curves of the combination of buspirone
with
melatonin are shown with the concentration response curves of buspirone or
melatonin alone.
The data is presented as a percent of neuronal or astrocyte positive control.
The data indicate
that the combination of buspirone with melatonin resulted in enhanced neuronal
differentiation and concomitant reduced astrocyte differentiation relative to
either agent
alone.
EXAMPLE 14
EFFECTS OF THE 5-HT1a AGONIST BUSPIRONE
IN COMBINATION WITH THE MELATONIN AGONIST
MELATONIN ON IN VIVO RAT BEHAVIOR AND NEUROGENESIS
105191 Male F344 rats were dosed lx per day for 21-days with 0 (vehicle only),
0.5 mg/kg
buspirone (n = 12 per dose group, i.p.), 3.0 mg/kg melatonin (n = 12 per dose
group, i.p.), or
the combination of the two drugs at the same doses. Twenty-four hours prior to
behavioral
testing, all food is removed from the home cage. At the time of testing a
single pellet is
placed in the center of a novel arena. Animals are placed in the corner of the
arena and the
latency (in time) to eat the pellet is recorded. Compounds are generally
administered 30
minutes prior to testing. Animals receive compound daily for 21 days and
testing is
performed on day 21. A decreased latency to eat the food pellet is indicative
of both
neurogenesis and antidepressant activity.
[0520] The results are in Figure 19 and show the mean latency to approach and
eat a food
pellet within the novel environment. Data are presented as latency to eat
expressed as percent
baseline. Melatonin or buspirone alone did not significantly reduce the
latency to eat the
food pellet. The combination of melatonin and buspirone resulted in a
significant decrease in
latency to eat the food pellet. The data indicate that the combination of
buspirone and
melatonin at doses that do not produce antidepressant activity (when each
compound is dosed
alone), results in significant antidepressant activity when administered in
combination.
[0521] For the in vivo neurogenesis assays, male F344 rats were dosed lx per
day for 28-
days with 0 (vehicle only), 0.5 mg/kg buspirone (n = 12 per dose group, i.p.),
3.0 mg/kg
melatonin (n = 12 per dose group, ip) or the combination of the two drugs at
the same doses.
BrdU was administered once daily between days 9 and 14 (100mg/kg/day, i.p.,
n=12 per dose
group). Figure 20 shows BrdU positive cell counts within the granule cell
layer of the
dentate gyrus. Data are presented as percent change in BrdU positive cells per
cubic mm
240
CA 02726300 2010-12-22
dentate gyrus. Melatonin or buspirone alone did not significantly change the
number of
BrdU positive cells. The combination of melatonin and buspirone resulted in a
significant
increase in BrdU positive cells compared to vehicle.
10522] In an additional experiment male F344 rats were dosed orally lx per day
for 21-
days with vehicle only (n=12), 12.5 mg/kg fluoxetine (n=12), 5 mg/kg buspirone
(n = 12), 1.0
mg/kg melatonin (n = 12), or the combination of the two drugs at the same
doses (n=12).
Twenty-four hours prior to behavioral testing, all food was removed from the
home cage. At
the time of testing a single pellet is placed in the center of a novel arena.
Animals were
placed in the corner of the arena and the latency (in time) to eat the pellet
was recorded.
Compounds were generally administered 30 minutes prior to testing. Animals
received
compound daily for 21 days and testing was performed on day 21. A decreased
latency to eat
the food pellet was indicative of both neurogenesis and antidepressant
activity.
105231 The results in Figure 54 show the mean latency to approach and eat a
food pellet
within the novel environment. Data are presented as latency to eat expressed
as percent
baseline. Fluoxetine showed a trend toward reduced latency to eat, but was not
significantly
different from the vehicle control. Also, melatonin or buspirone alone did not
significantly
reduce the latency to eat the food pellet. The combination of melatonin and
buspirone
resulted in a significant decrease in latency to eat the food pellet based on
students t-test
analysis. ANOVA analysis with Dunnett post hoc test showed a p value of 0.06.
The data
indicate that the combination of buspirone and melatonin at doses that do not
produce
antidepressant activity (when each compound is dosed as a monotherapy),
results in
significant antidepressant activity when administered in combination.
EXAMPLE 15
EFFECT OF COMBINED DOSING THE 5-HT1a AGONIST BUSPIRONE
AND MELATONIN ON BODY WEIGHT IN IN VIVO RODENT STUDIES
105241 Male Fischer F344 rats are chronically injected with test compound(s) +
vehicle or
vehicle only (negative control) once daily. Rats are weighed daily,
immediately prior to
injections. The results, shown in Figure 21, indicate that the combination of
melatonin and
buspirone resulted in decreased body weight over time.
241
CA 02726300 2010-12-22
EXAMPLE 16
EFFECTS OF THE 5-HT1a AGONIST BUSPIRONE IN
COMBINATION WITH THE GABA AGONIST BACLOFEN
ON DIFFERENTIATION OF HUMAN NEURAL STEM CELLS
[05251 Human neural stem cells (hNSCs) were isolated and grown in monolayer
culture,
plated, treated with varying concentrations of buspirone in the presence or
absence of the
GABA agonist baclofen, and stained with TUJ-1 antibody for the detection of
neuronal
differentiation or GFAP antibody for the detection of astrocyte
differentiation, as described
above. Mitogen-free test media with a positive control for neuronal
differentiation was used
along with basal media without growth factors as a negative control.
[05261 Results are shown in Figures 22 and 23, which show concentration
response curves
of neuronal and astrocyte differentiation respectively, after background media
values are
subtracted. The concentration response curves of the combination of buspirone
with baclofen
are shown with the concentration response curves of buspirone or baclofen
alone. The data is
presented as a percent of neuronal or astrocyte positive control. The data
indicate that the
combination of buspirone with baclofen resulted in selective reduction of
astrocyte
differentiation while retaining neuronal differentiation, indicating a lineage
specific
promotion of neuronal differentiation.
EXAMPLE 17
EFFECT OF 5-HT3 ANTAGONISTS ON
DIFFERENTIATION OF HUMAN NEURAL STEM CELLS
[05271 Human neural stem cells (hNSCs) were isolated and grown in monolayer
culture,
plated, treated with varying concentrations of a 5-HT3 antagonist and stained
with TUJ-1
antibody, as described above. Mitogen-free test media with a positive control
for neuronal
differentiation was used along with basal media without growth factors as a
negative control.
[05281 Results are shown in Figures 24, 25, 26, 27, 28, 29 and 30, which show
concentration response curves of neuronal or astrocyte differentiation after
background media
values are subtracted for the 5-HT3 antagonists azasetron, granisetron, and
ondansetron. The
effect of azasetron on toxicity/survival of neural stem cells is shown in
Figure 26. The data
are presented as percents of neuronal positive control. The data indicate that
azasetron,
granisetron, and ondansetron each promote differentiation of neural stem cells
into neurons,
and azasetron showed no detectable toxicity at concentrations up to 31.6 M.
242
CA 02726300 2010-12-22
EXAMPLE 18
EFFECT OF 5-HT4 AGONISTS ON NEURONAL
DIFFERENTIATION OF HUMAN NEURAL STEM CELLS
[05291 Human neural stem cells (hNSCs) were isolated and grown in monolayer
culture,
plated, treated with varying concentrations of a 5-HT4 agonist and stained
with TUJ-1
antibody, as described above. Mitogen-free test media with a positive control
for neuronal
differentiation was used along with basal media without growth factors as a
negative control.
105301 Results are shown in Figures 31, 32, 33, 34, 35 and 36, which show
concentration
response curves of neuronal or astrocyte differentiation after background
media values are
subtracted for the 5-HT4 agonists mosapride and cisapride. The effect of
mosapride on
toxicity/survival of neural stem cells is shown in Figure 33. The data are
presented as
percents of neuronal positive control. The data indicate that mosapride and
cisapride each
promote differentiation of neural stem cells into neurons, and mosapride
showed no
detectable toxicity at concentrations up to 31.6 M.
EXAMPLE 19
EFFECT OF SUMATRIPTAN ON NEURONAL
DIFFERENTIATION OF HUMAN NEURAL STEM CELLS
[05311 Human neural stem cells (hNSCs) were isolated and grown in monolayer
culture,
plated, treated with varying concentrations of the 5-HT1B/1D agonist
sumatriptan and stained
with TUJ-1 antibody, as described above. Mitogen-free test media with a
positive control for
neuronal differentiation was used along with basal media without growth
factors as a
negative control.
105321 Results are shown in Figure 37, which shows concentration response
curves of
neuronal differentiation after background media values are subtracted for
sumatriptan. The
data are presented as percents of neuronal positive control. The data indicate
that sumatriptan
promotes differentiation of neural stem cells into neurons.
EXAMPLE 20
EFFECT OF AGOMELATINE ON NEURONAL
DIFFERENTIATION OF HUMAN NEURAL STEM CELLS
105331 Human neural stem cells (hNSCs) were isolated and grown in monolayer
culture,
plated, treated with varying concentrations of the melatonin agonist
agomelatine and stained
243
CA 02726300 2010-12-22
with TUJ-l antibody, as described above. Mitogen-free test media with a
positive control for
neuronal differentiation was used along with basal media without growth
factors as a
negative control.
105341 Results are shown in Figure 38, which shows concentration response
curves of
neuronal differentiation after background media values are subtracted. The
data is presented
as a percent of neuronal positive control. The data indicate that agomelatine
promotes
differentiation of neural stem cells into neurons.
EXAMPLE 21
EFFECTS OF THE 5-HT1a AGONIST BUSPIRONE IN COMBINATION
WITH MODAFINIL ON DIFFERENTIATION OF HUMAN NEURAL STEM CELLS
[05351 Human neural stem cells (hNSCs) were isolated and grown in monolayer
culture,
plated, treated with varying concentrations of buspirone in the presence or
absence of
modafinil, and stained with TUJ-1 antibody for the detection of neuronal
differentiation or
GFAP antibody for the detection of astrocyte differentiation, as described
above. Mitogen-
free test media with a positive control for neuronal differentiation was used
along with basal
media without growth factors as a negative control.
[05361 Results are shown in Figures 39 and 40, which show concentration
response curves
of neuronal and astrocyte differentiation respectively, after background media
values are
subtracted. The concentration response curves of the combination of buspirone
with
modafinil are shown with the concentration response curves of buspirone or
modafinil alone.
The data is presented as a percent of neuronal or astrocyte positive control.
The data indicate
that the combination of buspirone with modafinil resulted in consistent
neuronal
differentiation with a simultaneous decrease in astrocyte differentiation
relative to that
produced by buspirone alone.
EXAMPLE 22
EFFECTS OF THE 5-HT3 ANTAGONIST
AZASETRON IN COMBINATION WITH THE 5-HT1a AGONIST
BUSPIRONE ON DIFFERENTIATION OF HUMAN NEURAL STEM CELLS
105371 Human neural stem cells (hNSCs) were isolated and grown in monolayer
culture,
plated, treated with varying concentrations of azasetron in the presence or
absence of
buspirone, and stained with TUJ-1 antibody for the detection of neuronal
differentiation or
244
CA 02726300 2010-12-22
GFAP antibody for the detection of astrocyte differentiation, as described
above. Mitogen-
free test media with a positive control for neuronal differentiation was used
along with basal
media without growth factors as a negative control.
[05381 Results are shown in Figure 41, which shows concentration response
curves of
neuronal differentiation after background media values are subtracted. The
concentration
response curves of the combination of azasetron with buspirone are shown with
the
concentration response curves either agent alone. The data is presented as a
percent of
neuronal positive control. The data indicate that the combination of azasetron
with buspirone
resulted in synergistically enhanced neuronal differentiation relative to that
that produced by
either agent alone.
EXAMPLE 23
EFFECTS OF THE 5-HT3 ANTAGONIST AZASETRON IN
COMBINATION WITH THE GABA RECEPTOR AGONIST
BACLOFEN ON DIFFERENTIATION OF HUMAN NEURAL STEM CELLS
[05391 Human neural stem cells (hNSCs) were isolated and grown in monolayer
culture,
plated, treated with varying concentrations of azasetron in the presence or
absence of
buspirone, and stained with TUJ-1 antibody for the detection of neuronal
differentiation or
GFAP antibody for the detection of astrocyte differentiation, as described
above. Mitogen-
free test media with a positive control for neuronal differentiation was used
along with basal
media without growth factors as a negative control.
105401 Results are shown in Figure 42, which shows concentration response
curves of
neuronal differentiation after background media values are subtracted. The
concentration
response curves of the combination of azasetron with baclofen are shown with
the
concentration response curves either agent alone. The data is presented as a
percent of
neuronal positive control. The data indicate that the combination of azasetron
with baclofen
resulted in synergistically enhanced neuronal differentiation relative to that
that produced by
either agent alone.
245
CA 02726300 2010-12-22
EXAMPLE 24
EFFECTS OF THE 5-HT3 ANTAGONIST
AZASETRON IN COMBINATION WITH THE ACE INHIBITOR
CAPTOPRIL ON DIFFERENTIATION OF HUMAN NEURAL STEM CELLS
105411 Human neural stem cells (hNSCs) were isolated and grown in monolayer
culture,
plated, treated with varying concentrations of azasetron in the presence or
absence of
captopril, and stained with TUJ- 1 antibody for the detection of neuronal
differentiation or
GFAP antibody for the detection of astrocyte differentiation, as described
above. Mitogen-
free test media with a positive control for neuronal differentiation was used
along with basal
media without growth factors as a negative control.
[05421 Results are shown in Figure 43, which shows concentration response
curves of
neuronal differentiation after background media values are subtracted. The
concentration
response curves of the combination of azasetron with captopril are shown with
the
concentration response curves either agent alone. The data is presented as a
percent of
neuronal positive control. The data indicate that the combination of azasetron
with captopril
resulted in synergistically enhanced neuronal differentiation relative to that
that produced by
either agent alone.
EXAMPLE 25
EFFECTS OF THE 5-HT3 ANTAGONIST
AZASETRON IN COMBINATION WITH THE PDE INHIBITOR
IBUDILAST ON DIFFERENTIATION OF HUMAN NEURAL STEM CELLS
105431 Human neural stem cells (hNSCs) were isolated and grown in monolayer
culture,
plated, treated with varying concentrations of azasetron in the presence or
absence of
ibudilast, and stained with TUJ-1 antibody for the detection of neuronal
differentiation or
GFAP antibody for the detection of astrocyte differentiation, as described
above. Mitogen-
free test media with a positive control for neuronal differentiation was used
along with basal
media without growth factors as a negative control.
105441 Results are shown in Figure 44, which shows concentration response
curves of
neuronal differentiation after background media values are subtracted. The
concentration
response curves of the combination of azasetron with ibudilast are shown with
the
concentration response curves either agent alone. The data is presented as a
percent of
neuronal positive control. The data indicate that the combination of azasetron
with ibudilast
246
CA 02726300 2010-12-22
resulted in synergistically enhanced neuronal differentiation relative to that
that produced by
either agent alone.
EXAMPLE 26
EFFECTS OF THE 5-HT3 ANTAGONIST AZASETRON IN
COMBINATION WITH THE MIXED OPIOID ANTAGONIST
NALTREXONE ON DIFFERENTIATION OF HUMAN NEURAL STEM CELLS
[05451 Human neural stem cells (hNSCs) were isolated and grown in monolayer
culture,
plated, treated with varying concentrations of azasetron in the presence or
absence of
naltrexone, and stained with TUJ-1 antibody for the detection of neuronal
differentiation or
GFAP antibody for the detection of astrocyte differentiation, as described
above. Mitogen-
free test media with a positive control for neuronal differentiation was used
along with basal
media without growth factors as a negative control.
105461 Results are shown in Figures 45 and 46, which show concentration
response curves
of neuronal and astrocyte differentiation respectively, after background media
values are
subtracted. The concentration response curves of the combination of buspirone
with
modafinil are shown with the concentration response curves of azasetron or
naltrexone alone.
The data is presented as a percent of neuronal or astrocyte positive control.
The data indicate
that the combination of azasetron with naltrexone resulted resulted in
synergistically
enhanced neuronal differentiation relative to that that produced by either
agent alone
concomitant with a simultaneous decrease in astrocyte differentiation relative
to that
produced by azasetron alone.
EXAMPLE 27
EFFECTS OF THE 5-HT3 ANTAGONIST AZASETRON IN COMBINATION
WITH FOLIC ACID ON DIFFERENTIATION OF HUMAN NEURAL STEM CELLS
105471 Human neural stem cells (hNSCs) were isolated and grown in monolayer
culture,
plated, treated with varying concentrations of azasetron in the presence or
absence of folic
acid, and stained with TUJ-1 antibody for the detection of neuronal
differentiation or GFAP
antibody for the detection of astrocyte differentiation, as described above.
Mitogen-free test
media with a positive control for neuronal differentiation was used along with
basal media
without growth factors as a negative control.
247
CA 02726300 2010-12-22
(05481 Results are shown in Figures 47 and 48, which show concentration
response curves
of neuronal and astrocyte differentiation respectively, after background media
values are
subtracted. The concentration response curves of the combination of buspirone
with
modafinil are shown with the concentration response curves of azasetron or
folic acid alone.
The data is presented as a percent of neuronal or astrocyte positive control.
The data indicate
that the combination of azasetron with folic acid resulted resulted in
synergistically enhanced
neuronal differentiation relative to that that produced by either agent alone
concomitant with
a simultaneous decrease in astrocyte differentiation relative to that produced
by azasetron
alone.
EXAMPLE 28
EFFECTS OF THE 5-HT3 ANTAGONIST
AZASETRON IN COMBINATION WITH GABAPENTIN
ON DIFFERENTIATION OF HUMAN NEURAL STEM CELLS
105491 Human neural stem cells (hNSCs) were isolated and grown in monolayer
culture,
plated, treated with varying concentrations of azasetron in the presence or
absence of
gabapentin, and stained with TUJ-1 antibody for the detection of neuronal
differentiation or
GFAP antibody for the detection of astrocyte differentiation, as described
above. Mitogen-
free test media with a positive control for neuronal differentiation was used
along with basal
media without growth factors as a negative control.
105501 Results are shown in Figure 49, which shows concentration response
curves of
neuronal differentiation after background media values are subtracted. The
concentration
response curves of the combination of azasetron with gabapentin are shown with
the
concentration response curves either agent alone. The data is presented as a
percent of
neuronal positive control. The data indicate that the combination of azasetron
with
gabapentin resulted in synergistically enhanced neuronal differentiation
relative to that that
produced by either agent alone.
EXAMPLE 29
EFFECTS OF THE 5-HT3 ANTAGONIST AZASETRON
IN COMBINATION WITH METHYLPHENIDATE ON
DIFFERENTIATION OF HUMAN NEURAL STEM CELLS
105511 Human neural stem cells (hNSCs) were isolated and grown in monolayer
culture,
plated, treated with varying concentrations of azasetron in the presence or
absence of
248
CA 02726300 2010-12-22
methylphenidate, and stained with TUJ-1 antibody for the detection of neuronal
differentiation or GFAP antibody for the detection of astrocyte
differentiation, as described
above. Mitogen-free test media with a positive control for neuronal
differentiation was used
along with basal media without growth factors as a negative control.
105521 Results are shown in Figures 50 and 51, which show concentration
response curves
of neuronal and astrocyte differentiation respectively, after background media
values are
subtracted. The concentration response curves of the combination of azasetron
with
methylphenidate are shown with the concentration response curves of azasetron
or
methylphenidate alone. The data is presented as a percent of neuronal or
astrocyte positive
control. The data indicate that the combination of azasetron with
methylphenidate resulted
resulted in synergistically enhanced neuronal differentiation relative to that
that produced by
either agent alone concomitant with a simultaneous decrease in astrocyte
differentiation
relative to that produced by azasetron alone.
EXAMPLE 30
EFFECTS OF THE 5-HT3 ANTAGONIST AZASETRON
IN COMBINATION WITH THE ANTI-PSYCHOTIC DRUG
CLOZAPINE ON DIFFERENTIATION OF HUMAN NEURAL STEM CELLS
105531 Human neural stem cells (hNSCs) were isolated and grown in monolayer
culture,
plated, treated with varying concentrations of azasetron in the presence or
absence of
clozapine, and stained with TUJ-1 antibody for the detection of neuronal
differentiation or
GFAP antibody for the detection of astrocyte differentiation, as described
above. Mitogen-
free test media with a positive control for neuronal differentiation was used
along with basal
media without growth factors as a negative control.
105541 Results are shown in Figure 52, which shows concentration response
curves of
neuronal differentiation after background media values are subtracted. The
concentration
response curves of the combination of azasetron with clozapine are shown with
the
concentration response curves either agent alone. The data is presented as a
percent of
neuronal positive control. The data indicate that the combination of azasetron
with clozapine
resulted in synergistically enhanced neuronal differentiation relative to that
that produced by
either agent alone.
249
CA 02726300 2010-12-22
EXAMPLE 31
EFFECTS OF THE 5-HT3 ANTAGONIST
AZASETRON IN COMBINATION WITH THE GABA MODULATOR
CARBAMAZEPINE ON DIFFERENTIATION OF HUMAN NEURAL STEM CELLS
[05551 Human neural stem cells (hNSCs) were isolated and grown in monolayer
culture,
plated, treated with varying concentrations of azasetron in the presence or
absence of
carbamazepine, and stained with TUJ-1 antibody for the detection of neuronal
differentiation
or GFAP antibody for the detection of astrocyte differentiation, as described
in U.S.
Provisional Application No. 60/697,905 (incorporated by reference). Mitogen-
free test media
with a positive control for neuronal differentiation was used along with basal
media without
growth factors as a negative control.
105561 Results are shown in Figure 53, which shows concentration response
curves of
neuronal differentiation after background media values are subtracted. The
concentration
response curves of the combination of azasetron with carbamazepine are shown
with the
concentration response curves either agent alone. The data is presented as a
percent of
neuronal positive control. The data indicate that the combination of azasetron
with
carbamazepine resulted in synergistically enhanced neuronal differentiation
relative to that
that produced by either agent alone.
EXAMPLE 32
DETERMINATION OF SYNERGY
105571 The presence of synergy was determined by use of a combination index
(CI). The
CI based on the EC50 was used to determine whether a pair of compounds had an
additive,
synergistic (greater than additive), or antagonistic effect when run in
combination. The Cl is
a quantitative measure of the nature of drug interactions, comparing the
EC50's of two
compounds, when each is assayed alone, to the EC50 of each compound when
assayed in
combination. The combination index (CI) is equal to the following formula:
Cl + C2 + C1( * C2)
IC l IC2 (IC 1 * IC2)
Where Cl and C2 are the concentrations of a first and a second compound,
respectively, resulting in 50% activity in neuronal differentiation when
assayed in
combination; and IC I and IC2 are the concentrations of each compound
resulting in 50%
activity when assayed independently. A Cl of less than 1 indicates the
presence of synergy; a
250
CA 02726300 2010-12-22
Cl equal to I indicates an additive effect; and a Cl greater than I indicates
antagonism
between the two compounds.
[05581 In addition, the CI value allowed for the relative comparison of the
anti-astrogenic
effect of compounds on the astrogenesis induced by a 5HT agent. The greater
the Cl value
the greater the reduction of induced astrogenesis. Non-limiting examples of
combinations of
a 5HT agent and an additional agent as described herein were observed to
result in synergistic
activity. The exemplary results are shown in Table 1.
105591 Table 1. Combination Index for Azasetron (5HT3 Antagonist) Combinations
Combination Cl
Azasetron + Buspirone 0.18
Azasetron + Baclofen 0.08
Azasetron + Captopril 0.47
Azasetron + Ibudilast 0.17
Azasetron + Naltrexone 0.45
Azasetron + Folic Acid 0.08
Azasetron + Gabapentin 0.24
Azasetron + Methylphenidate 0.06
Azasetron + Clozapine 0.06
Azasetron + Carbemazepine 0.09
[05601 As the Cl is less than 1 for each of these combinations, the two
compounds have a
synergistic effect on neuronal differentiation.
105611 The above is based on the selection of EC50 as the point of comparison
for the two
compounds. The comparison is not limited by the point used, but rather the
same comparison
may be made at another point, such as EC20, EC30, EC40, EC60, EC70, EC80, or
any other EC
value above, below, or between any of those points.
EXAMPLE 33
DOSE RANGING AND DOSE RATIOS FOR THE COMBINATIONS OF 5HT3
ANTAGONISTS (AZASETRON, GRANISETRON AND ONDANSETRON) WITH
NALTREXONE
105621 To determine the most efficacious dose and dose ratio of a 5HT3
antagonist
(azasetron, granisetron and ondansetron) with naltrexone for future
preclinical and clinical
studies, dose ranging studies were conducted examining the synergy for
neurogenesis as well
as the anti-astrogenic effect of naltrexone. For the ratios of 30:1, 10:1,
3:1, 1:1, and 1:3
251
CA 02726300 2010-12-22
(5HT3: naltrexone ratio), the 5HT3 antagonist concentration ranged from 0.01
M to 31.6 M
for each dose response assay. The naltrexone concentration was varied based on
the
respective ratio. Due to solubility issues for naltrexone, the 5HT3 antagonist
concentration
range for the 1:10 and 1:32 ratios (5HT3: naltrexone ratio), was decreased to
0.001 M to 3.2
M for these dose response assays with the naltrexone concentration adjusted
accordingly to
the specified ratio. Individual dose response curves were prepared for each
concentration
ratio as previously described with cells stained with TUJ-1 antibody for the
detection of
neuronal differentiation or GFAP antibody for the detection of astrocyte
differentiation (see
Example 16).
105631 Analysis of the azasetron + naltrexone combination showed synergy for
inducing
neurogenesis at the 10:1, 3:1, 1:1, 1:3, 1:10 and 1:30 ratios and astrocyte
suppression at the
30:1, 10:1, 3:1, 1:1, 1:3 and 1:10 ratios (Figures 57A and 57B; Table 2).
Analysis of the
granisetron + naltrexone combination showed synergy for inducing neurogenesis
at the 30:1,
10:1, 3:1, 1:1, 1:3, 1:10 and 1:30 ratios and astrocyte suppression at the
3:1, 1:1, 1:3 and 1:10
ratios (Figures 58A and 58B; Table 2). Analysis of the ondansetron +
naltrexone
combination showed synergy for inducing neurogenesis at the 30:1, 10:1, 3:1,
1:1, 1:3, and
1:30 ratios and astrocyte suppression at the 30:1, 10:1, 3:1, 1:1, 1:3 and
1:10 ratios (Figures
59A and 59B; Table 2).
[05641 Table 2. Neurogenic and Astrogenic Effects of 5HT3 Antagonists in
Combination
with Naltrexone Over Varying Dose Ratios (CI Values)
Azasetron Ondansetron Granisetron
5HT:Naltrex Neuro Astro Neuro Astro Neuro Astro
ratio
30:1 1.18 25.3 0.78 35.7 0.11 1.07
10:1 0.62 25.3 0.36 35.7 0.19 1.84
3:1 0.14 25.3 0.44 35.7 0.40 3.70
1:1 0.91 25.3 0.18 35.7 0.19 14.9
1:3 0.53 25.3 0.14 35.7 0.28 14.9
1:10 0.84 8.69 3.00 12.0 0.39 5.41
1:30 0.45 NC 0.45 NC 0.04 NC
Abbreviations: Neuro (neurogenesis); Astro (astrogenesis); Naltrex
(naltrexone)
NC - not calculable due to unachievable concentrations of naltrexone for the
assay
A CI of less than 1 indicates the presence of synergy; a Cl equal to 1
indicates an additive
effect; and a Cl greater than 1 indicates antagonism between the two
compounds.
252
CA 02726300 2010-12-22
[005651 Analysis of the granisetron + naltrexone combination showed synergy
for inducing
neurogenesis at the 30:1, 10:1, 3:1, 1:1, 1:3, 1:10 and 1:30 ratios and
astrocyte suppression at
the 3:1, 1:1, 1:3 and 1:10 ratios (Figures 58A and 58B). Analysis of the
ondansetron +
naltrexone combination showed synergy for inducing neurogenesis at the 30:1,
10:1, 3:1, 1:1,
1:3, and 1:30 ratios and astrocyte suppression at the 30:1, 10:1, 3:1, 1:1,
1:3 and 1:10 ratios
(Figures 59A and 59B). The data in Table 2 is depicted in graphic form in
Figures 57-59.
EXAMPLE 34
EFFECTS OF THE 5-HT3 ANTAGONIST ONDANSETRON
IN COMBINATION WITH THE NALTREXONE
ON IN VIVO RAT BEHAVIOR
1005661 Male F344 rats were dosed intraperitoneally (i.p.) Ix per day for 21-
days with
vehicle only (n = 10), 12.5 mg/kg imipramine (n =9), 3.33 mg/kg ondansetron (n
= 10), 1.0
mg/kg naltrexone (n = 9), or the combination of the two drugs at the same
doses (n = 7) or
combined at 1.0 mg/kg ondansetron with 0.3 mg/kg naltrexone. Behavioral
testing was
carried out as described in Example 14. Results shown in this Fig. 60 indicate
the mean
latency to approach and eat a food pellet within the novel environment.
Compared to vehicle
control, animals treated with ondansetron + naltrexone (3.33+1.0 mg/kg, i.p.)
had a
statistically significant decrease in latency to eat (p<0.01, unpaired
students t-tests).
Treatment for 28-day with naltrexone (1.0 mg/kg, i.p.) also resulted in a
statistically
significant decrease in latency to eat. (p<0.05, unpaired students t-tests).
Animals treated
with ondansetron + naltrexone at the lower dose (1.0+0.3 mg/kg, i.p.) had a
decreased latency
to eat (p=0.07, unpaired students t-tests). The positive control Imipramine
performed as
expected and resulted in a statistically significant decrease in latency to
eat (p<0.001,
unpaired students t-tests). The data shows that a synergistic effect was
achieved with the
combination of ondansetron and naltrexone at the higher dose combination
(3.33. and 1.0
mg/kg respectively) producing a reduction in latency to eat greater than the
results achieved
in combining the individual scores for the drugs alone.
253
CA 02726300 2010-12-22
EXAMPLE 35
CLINICAL TRIAL EXAMINING THE EFFICACY
OF THE COMBINATION OF BUSPIRONE AND MELATONIN
IN PATIENTS WITH MAJOR DEPRESSIVE DISORDER (MDD)
[0567] Based on dose-ranging efficacy studies in pre-clinical assays (GFAP to
Tuj-1 ratio
and in vivo efficacy), an optimal clinical dose was determined to be 15 mg of
buspirone in
combination with 3 mg of melatonin. Doses in this range were found to be safe
and well
tolerated in humans.
105681 A 6-week double-blind, placebo-controlled, randomized study (2:1:1) of
15 mg of
buspirone with 3 mg melatonin (combination treatment) compared to placebo or
15 mg of
buspirone alone nightly, at nine clinical trial sites was conducted. Buspirone
alone was
included in the study because of reports that doses above 40 mg may be
beneficial for MDD.
Melatonin is a sleep aid but has no effect on other depressive symptoms (Wirz-
Justice et al., J
Psychiatr Res 24:129-37, 1990; Dolberg et al., Am J Psychiatry 155:1119-21,
1998; and
Buscemi et al., BMJ 332:385-93, 2006). Based on the reported lack of efficacy
of melatonin
for the treatment of depression, the effect of melatonin alone was not
studied. 142 patients
that met DSM-IV criteria for MDD with a minimum score of 14 on the Quick
Inventory of
Depressive Symptoms-Self Rated Form (QIDSR-16) consented to participate. There
were no
differences between the three treatment groups with regard to age, gender,
race, ethnicity or
disease severity. 112 patients completed the study. On the primary efficacy
measure, the
Clinical Global Impression of Improvement Scale (CGI-I) patients receiving the
combination
treatment achieved significantly greater improvement compared to placebo or
buspirone
alone (Figure 56A).
[0569] A Responder analysis, in which patients with a CGI-I <2 were considered
Responders, was also conducted. Patients receiving the combination treatment
did
significantly better on the CGI-I scale compared to patients receiving either
placebo or
buspirone alone (Figure 56B, X2= 7.29; p<0.03). Among the patients that
completed the
study, 36 of 54 patients (67%) in the combination group were Responders
compared to 12 of
30 patients (40%) receiving placebo (Fisher's exact test; p=0.022) and 12 of
28 patients
(43%) receiving buspirone alone (Fisher's exact test; p=0.058). The clinical
response to
buspirone alone did not differ from placebo. When the placebo and buspirone
alone groups
254
CA 02726300 2010-12-22
were pooled (as per the statistical plan), the CGI-I Responder analysis for
the combination
treatment was significantly greater than the pooled group (p=0.009).
[05701 Additional efficacy instruments were used, including the CGI-Severity
(CGI-S),
Inventory of Depressive Symptoms (IDS-c30), QIDS-SR16, and the Hamilton
Anxiety
[05711 Scale (Ham-A) Scales. After 6 weeks of treatment, the combination
treatment was
significantly better than the pooled placebo and the buspirone-alone groups
based on the
CGI-S (ANCOVA; p<0.05), IDSc3O (p<0.05), and the Ham-A (p<0.05) scales (Table
3).
There was a non-significant trend to improved efficacy of the combination
treatment on the
QIDS-SR16 (p<0.10) scale.
105721 Table 3. Analysis of the Change from Baseline HAM-A Using ANCOVA
(Computer Population) Week 6
Visit # n Point SE 95% Cl p
Estimate value
Placebo 30 6.51 1.16 4.2-8.8
Buspirone 28 6.69 1.20 4.3-9.1
LS Means Buspirone + 53 9.04 0.87 7.3-10.8
Melatonin
Buspirone + 58 6.60 0.83 5.0-8.2
Placebo
B+M vs +2.53 1.45 0.083
(Week 6) Placebo
B+M vs +2.35 1.48 0.115
Diff. of Buspirone
LS Means Buspirone vs +0.18 1.66 0.915
Placebo
B+M vs
Buspirone + +2.44 1.21 0.045
Placebo
105731 In summary, the combination of buspirone and melatonin produced a
significant
antidepressant response in individuals with MDD, as well as an increase in the
fraction of
patients who were Responders when compared to placebo or buspirone alone. This
study
demonstrates that rational drug discovery utilizing pre-clinical neurogenesis
assays can be
used to identify treatments for MDD.
255
CA 02726300 2010-12-22
[0574] All references cited herein, including patents, patent applications,
and publications,
are hereby incorporated by reference in their entireties, whether previously
specifically
incorporated or not.
[05751 Having now fully provided the instant disclosure, it will be
appreciated by those
skilled in the art that the same can be performed within a wide range of
equivalent
parameters, concentrations, and conditions without departing from the spirit
and scope of the
disclosure and without undue experimentation.
[05761 While the disclosure has been described in connection with specific
embodiments
thereof, it will be understood that it is capable of further modifications.
This application is
intended to cover any variations, uses, or adaptations of the disclosure
following, in general,
the disclosed principles and including such departures from the disclosure as
come within
known or customary practice within the art to which the disclosure pertains
and as may be
applied to the essential features hereinbefore set forth.
256
